WO2011159633A1 - Inhalable formulations of lysophosphatdic acid receptor antagonists - Google Patents

Inhalable formulations of lysophosphatdic acid receptor antagonists Download PDF

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Publication number
WO2011159633A1
WO2011159633A1 PCT/US2011/040233 US2011040233W WO2011159633A1 WO 2011159633 A1 WO2011159633 A1 WO 2011159633A1 US 2011040233 W US2011040233 W US 2011040233W WO 2011159633 A1 WO2011159633 A1 WO 2011159633A1
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substituted
lpa
unsubstituted
alkyl
inhalable formulation
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PCT/US2011/040233
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French (fr)
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Thomas Jon Seiders
John Howard Hutchinson
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Amira Pharmaceuticals, Inc.
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Publication of WO2011159633A1 publication Critical patent/WO2011159633A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles

Definitions

  • inhalable formulations that include at least one lysophosphatidic acid (LPA) receptor antagonist, and methods of using such formulations to treat or prevent diseases, disorders or conditions mediated by one or more of the LPA receptors.
  • LPA lysophosphatidic acid
  • LPA Lysophosphatidic acid
  • LPA l5 LPA2, LP A3, LPA 4 , LPA5 activates intracellular signaling pathways and produces a variety of biological responses.
  • Inhaled formulations of LPA receptor antagonists, administered to the lungs of a mammal, are used to prevent, ameliorate or treat LPA-dependent or LPA-mediated diseases or conditions.
  • the formulations described herein are suitable for oral or nasal inhalation.
  • the inhalable formulations described herein include one or more LPA receptor antagonists and allow for rapid delivery of a therapeutically effective amount of an LPA receptor antagonist into the circulatory system and/or target organ (e.g., the lungs) of a mammal in need thereof.
  • Pulmonary administration of an inhalable formulation described herein reverses, ameliorates, treats or prevents diseases or conditions in which the physiological activity of LPA is involved in the etiology or pathology of a disease or condition, or is otherwise associated with at least one symptom of a disease or condition.
  • an inhalable formulation comprising an LPA receptor antagonist and at least one pharmaceutically acceptable excipient, wherein the formulation is in a form suitable for administration to the lungs of a mammal.
  • the inhalable formulation comprising an LPA receptor antagonist in an amount effective for the treatment of an LPA-dependent or LPA-mediated disease or condition.
  • the LPA-dependent or LPA-mediated disease or condition is a disease or condition as described herein.
  • the inhalable formulation is a solution, suspension, emulsion, colloidal dispersion, or dry powder, wherein the formulation is suitable for administration to the lungs of a mammal.
  • an inhalable formulation comprising an LPA receptor antagonist in an amount effective for the treatment of an LPA-dependent or LPA-mediated disease or condition, and at least one pharmaceutically acceptable excipient to provide a solution, suspension, emulsion, colloidal dispersion, or dry powder, wherein the formulation is in a form suitable for administration to the lungs of a mammal.
  • an inhalable formulation comprising an LPA receptor antagonist in an amount effective for antagonizing LPA receptors, and at least one pharmaceutically acceptable excipient to provide a solution, suspension, emulsion, colloidal dispersion, or dry powder for administration to the lungs of a mammal.
  • the LPA-dependent or LPA-mediated disease or condition is lung cancer, asthma, obstructive pulmonary disease (COPD), pulmonary fibrosis, idiopathic pulmonary fibrosis, radiation induced fibrosis, silicosis, asbestos induced pulmonary or pleural fibrosis, acute lung injury, acute respiratory distress syndrome (ARDS), usual interstitial pneumonia (UIP), cystic fibrosis, Chronic lymphocytic leukemia (CLL)-associated fibrosis, Hamman-Rich syndrome, Caplan syndrome, coal worker's pneumoconiosis, cryptogenic fibrosing alveolitis, obliterative bronchiolitis, chronic bronchitis, emphysema, Wegner's granulamatosis, or interstitial lung disease.
  • COPD obstructive pulmonary disease
  • pulmonary fibrosis idiopathic pulmonary fibrosis
  • radiation induced fibrosis silicosis
  • the LPA-dependent or LPA-mediated disease or condition is lung cancer, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), usual interstitial pneumonia (UIP), cystic fibrosis, Chronic lymphocytic leukemia (CLL)-associated fibrosis, Hamman-Rich syndrome, Caplan syndrome, coal worker's pneumoconiosis, silicosis, interstitial lung disease, asbestos induced pulmonary or pleural fibrosis, cryptogenic fibrosing alveolitis, or obliterative bronchiolitis.
  • lung cancer pulmonary fibrosis
  • IPF idiopathic pulmonary fibrosis
  • UFP usual interstitial pneumonia
  • cystic fibrosis cystic fibrosis
  • CLL Chronic lymphocytic leukemia
  • Hamman-Rich syndrome Caplan syndrome
  • coal worker's pneumoconiosis silicosis
  • interstitial lung disease asbestos induced pulmonary or ple
  • the LPA-dependent or LPA-mediated disease or condition is idiopathic pulmonary fibrosis. In some embodiments, the LPA-dependent or LPA-mediated disease or condition is cystic fibrosis.
  • the LPA-dependent or LPA-mediated disease or condition is Chronic lymphocytic leukemia (CLL)-associated fibrosis.
  • CLL Chronic lymphocytic leukemia
  • the LPA-dependent or LPA-mediated disease or condition is silicosis.
  • the LPA-dependent or LPA- mediated disease or condition is asthma or chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the inhalable formulation comprises an LPA receptor antagonist that has a structure of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI) or Formula (VII), or a pharmaceutically acceptable salt thereof.
  • the inhalable formulation comprises an LPA receptor antagonist that has a structure of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the inhalable formulation comprises an LPA receptor antagonist that has a structure of Formula (II), or a pharmaceutically acceptable salt thereof.
  • the inhalable formulation comprises an LPA receptor antagonist that has a structure of Formula (III), or a pharmaceutically acceptable salt thereof.
  • the inhalable formulation comprises an LPA receptor antagonist that has a structure of Formula (IV), or a pharmaceutically acceptable salt thereof. In some embodiments, the inhalable formulation comprises an LPA receptor antagonist that has a structure of Formula (V), or a pharmaceutically acceptable salt thereof. In some embodiments, the inhalable formulation comprises an LPA receptor antagonist that has a structure of Formula (VI) or a pharmaceutically acceptable salt thereof. In some embodiments, the inhalable formulation comprises an LPA receptor antagonist that has a structure of Formula (VII), or a pharmaceutically acceptable salt thereof.
  • the inhalable formulation comprises an LPA receptor antagonist wherein the LPA receptor antagonist is an antagonist of one or more LPA receptors selected from LPAi, LPA 2 , LPA 3 , LPA 4 and LPA 5 .
  • the inhalable formulation comprises an LPA receptor antagonist wherein the LPA receptor antagonist is an antagonist of LPA i.
  • the inhalable formulation comprises an LPA receptor antagonist that is a selective LPAi antagonist.
  • the inhalable formulation comprises an LPAi antagonist that is described in US Provisional Application no. 61/122,568; US Provisional Application no. 61/183,785; US Patent Application no. 12/638,702; US Provisional Application no. 61/121,862; US Provisional Application no. 61/231,282; US Provisional Application no. 61/247,681; US Provisional Application no. 61/2472877; International patent application no. PCT/US2010/44284; International patent application no. PCT/US2010/51199; International patent application no. PCT/US2010/51150; US Patent Application no. 12/896,080; International patent application no. PCT/US2010/50786;
  • the inhalable formulation comprises an LPAi and LPA 3 dual antagonist. In some embodiments, the inhalable formulation comprises an LPAi and LPA 2 dual antagonist. In some embodiments, the inhalable formulation comprises a selective LPAi antagonist.
  • the inhalable formulation comprises an LPA receptor antagonist that is selected from compounds described in U.S. Patent Nos. 6,964,975; 7,288,558 and U.S. Application Publication No. 2006/0194850, or pharmaceutically acceptable salt, or N-oxide thereof.
  • herein is a method of treating an LPA-dependent or LPA- mediated disease or condition, comprising administering to a mammal in need thereof a
  • Also provided herein is a method of antagonizing LPA receptors in a mammal, comprising administering to the mammal an inhalable formulation described herein.
  • a method of antagonizing LPA receptors in the lungs of a mammal comprising
  • the mammal has at least one symptom of an LPA-dependent or LPA-mediated disease or condition. In one aspect, the mammal has at least one symptom of an LPA-dependent or LPA-mediated disease or condition that affects the lungs. In one aspect, the mammal is a human. In some embodiments, the method comprises administration of an inhalable formulation that is in the form of a solution, suspension, emulsion, colloidal dispersion, spray, dry powder, aerosol, or drops, or combinations thereof.
  • the LPA-dependent or LPA-mediated disease or condition is lung cancer, asthma, obstructive pulmonary disease (COPD), pulmonary fibrosis, idiopathic pulmonary fibrosis, radiation induced fibrosis, silicosis, asbestos induced pulmonary or pleural fibrosis, acute lung injury, acute respiratory distress syndrome (ARDS), usual interstitial pneumonia (UIP), cystic fibrosis, Chronic lymphocytic leukemia (CLL)-associated fibrosis, Hamman-Rich syndrome, Caplan syndrome, coal worker's pneumoconiosis, cryptogenic fibrosing alveolitis, obliterative bronchiolitis, chronic bronchitis, emphysema, Wegner's
  • the LPA-dependent or LPA- mediated disease or condition is lung cancer, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), usual interstitial pneumonia (UIP), cystic fibrosis, Chronic lymphocytic leukemia (CLL)-associated fibrosis, Hamman-Rich syndrome, Caplan syndrome, coal worker's pneumoconiosis, silicosis, interstitial lung disease, asbestos induced pulmonary or pleural fibrosis, cryptogenic fibrosing alveolitis, or obliterative bronchiolitis.
  • lung cancer pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), usual interstitial pneumonia (UIP), cystic fibrosis, Chronic lymphocytic leukemia (CLL)-associated fibrosis, Hamman-Rich syndrome, Caplan syndrome, coal worker's pneumoconiosis, silicosis, interstitial lung disease, asbestos induced pulmonary or
  • the LPA-dependent or LPA-mediated disease or condition is idiopathic pulmonary fibrosis. In some embodiments of the methods described herein, the LPA-dependent or LPA-mediated disease or condition is cystic fibrosis. In some embodiments of the methods described herein, the LPA-dependent or LPA-mediated disease or condition is Chronic lymphocytic leukemia (CLL)-associated fibrosis. In some embodiments of the methods described herein, the LPA-dependent or LPA-mediated disease or condition is silicosis.
  • CLL Chronic lymphocytic leukemia
  • the LPA-dependent or LPA-mediated disease or condition is asthma or chronic obstructive pulmonay disease (COPD).
  • COPD chronic obstructive pulmonay disease
  • the inhalable formulation is administered before contact with an irritant and/or allergen. In some embodiments of the methods described herein, the inhalable formulation is administered after contact with an irritant and/or allergen. [0024] In some embodiments the inhalable formulation comprises at least one pharmaceutically acceptable excipient selected from pH-modifying agents, tonicity agents, propellants, preservatives, and surfactants.
  • the inhalable formulation is administered with an atomizer, an insufflator, a nebulizer, a vaporizer, or a metered dose inhaler.
  • the inhalable formulation is inhaled nasally or orally.
  • the inhalable formulation comprises LPA receptor antagonist(s) wherein the particle size of the LPA receptor antagonist is about 20-60 ⁇ in diameter.
  • the inhalable formulation comprises LPA receptor antagonist(s) wherein the particle size of the LPA receptor antagonist is about 5-20 ⁇ in diameter.
  • Also provided herein is a method of increasing the concentration of an LPA receptor antagonist in the lungs of a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of an inhalable formulation described herein.
  • the mammal has at least one symptom of an LPA-dependent or LPA-mediated disease or condition affecting the lungs.
  • the mammal has at least one symptom of an LPAi- dependent or LPA mediated disease or condition affecting the lungs.
  • the inhalable formulations provided herein are used to antagonize at least one LPA receptor in the lungs of a mammal in need thereof. In some embodiments, inhalable formulations provided herein are used to antagonize at least one LPA receptor for the treatment of a disease or condition that would benefit from antagonizing at least one LPA receptor in the lungs of a mammal in need thereof.
  • the LPA receptor antagonized is LPAi. In one aspect the LPA receptors antagonized are LPAi and LPA 3 .
  • Articles of manufacture which include packaging material, inhalable formulations within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, tautomers, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, used for inhibiting the activity of at least one LPA receptor, or for the treatment, prevention or amelioration of one or more symptoms of a disease or condition that would benefit from inhibition of the activity of at least one LPA receptor, are provided.
  • Lysophospholipids are membrane-derived bioactive lipid mediators. Lysophospholipids include, but are not limited to, lysophosphatidic acid (l-acyl-2-hydroxy-s «-glycero-3 -phosphate; LPA), sphingosine 1 -phosphate (S IP), lysophosphatidylcholine (LPC), and
  • the lysophospho lipid LPA acts through sets of specific G protein-coupled receptors (GPCRs) in an autocrine and paracrine fashion.
  • GPCRs G protein-coupled receptors
  • LPA binding to its cognate GPCRs activates intracellular signaling pathways that mediate a variety of biological responses, including e.g., beneficial processes such as wound healing, angiogenesis, myelination, immunity and/or neurogenesis.
  • LPA binding to its cognate GPCRs also plays a role in physiological pathways related to inflammation and/or carcinogenesis. The cellular responses to LPA are predominantly mediated through the lysophosphatidic acid receptors.
  • LPA binding to LPA receptors mediates the pathology of disorders, diseases or conditions associated with, for example, aberrant wound healing, cell proliferation, block in apoptosis, and/or inflammation.
  • LPA receptor antagonists disrupt LPA-dependent or LPA-mediated biological processes and reverse, ameliorate, prevent and/or treat LPA-dependent or LPA-mediated diseases or conditions.
  • LPA receptor antagonists in the manufacture of medicaments suitable for inhalable administration to the lungs of a mammal for the treatment or prevention of LPA-dependent or LPA-mediated diseases, disorders or conditions.
  • the LPA receptor antagonists are LPAi receptor antagonists.
  • the LPA receptor antagonists are dual LPAi and LP A3 receptor antagonists.
  • pulmonary administration of any inhaled formulation described herein antagonizes LPA receptors locally in the lungs.
  • inhalable formulations for administration to the lungs of a mammal that include an LPA receptor antagonist compound for treating an LPA- dependent or LPA-mediated disease, disorder or condition.
  • inhalable administration of an LPA receptor antagonist compound to the lungs of a mammal minimizes systemic absorption of the LPA receptor antagonist compound.
  • treatment of LPA-dependent or LPA-mediated diseases, disorders or conditions with an inhalable formulation described herein reduces possible side effects associated with systemic administration of an LPA receptor antagonist compound.
  • Activated platelets play pivotal roles in wound healing processes by releasing bioactive mediators to induce cell proliferation, cell migration, blood coagulation, and angiogenesis.
  • LPA is one such mediator that is released from activated platelets; this induces platelet aggregation along with mitogenic/migration effects on the surrounding cells, such as endothelial cells, smooth muscle cells, fibroblasts, and keratinocytes.
  • LPA regulates many important functions of fibroblasts in wound healing, including proliferation, migration, differentiation and contraction. Fibroblast proliferation is required in wound healing in order to fill an open wound. In contrast, fibrosis is characterized by intense proliferation and accumulation of myofibroblasts that actively synthesize ECM and proinflammatory cytokines. LPA can either increase or suppress the proliferation of cell types important in wound healing, such as epithelial and endothelial cells (EC),macrophages, keratinocytes, and fibroblasts.
  • EC epithelial and endothelial cells
  • keratinocytes keratinocytes
  • fibroblasts A role for LPAi in LPA-induced proliferation was provided by the observation that LPA-stimulated proliferation of fibroblasts isolated from LPAi receptor null mice was attenuated (Mills et al, Nat Rev. Cancer 2003; 3: 582-591). LPA induces cytoskeletal changes that are integral to fibroblast adhesion, migration, differentiation and contraction
  • Tissue injury initiates a complex series of host wound-healing responses; if successful, these responses restore normal tissue structure and function. Aberrant responses can lead to tissue fibrosis and loss of function.
  • Fibrotic lung diseases such as idiopathic pulmonary fibrosis (IPF) are associated with high morbidity and mortality.
  • LPAi -receptor stimulation in the lung causes vascular leakage and increased fibroblast recruitment, both profibrotic events.
  • the LP A- LPAi pathway has a role in mediating fibroblast migration and vascular leakage in IPF. The end result is an aberrant healing process and consequent fibrosis.
  • the LPAi receptor is the LPA receptor most highly expressed on fibroblasts obtained from patients with IPF. In human subjects with IPF, high LPA levels are observed in bronchoalveolar lavage samples compared with healthy controls.
  • the LP A- LPAi pathway is crucial in fibroblast recruitment and vascular leakage in pulmonary fibrosis. In certain instances, treatment of IPF and other fibrotic conditions with an LPA receptor antagonist reverses the profibrotic aberrant wound healing processes.
  • fibrosis refers to conditions that are associated with the abnormal accumulation of cells and/or fibronectin and/or collagen and/or increased fibroblast recruitment and include but are not limited to fibrosis of individual organs or tissues such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and digestive tract.
  • Exemplary diseases, disorders, or conditions that involve fibrosis include, but are not limited to: Lung diseases associated with fibrosis, e.g., lung cancer, asthma, obstructive pulmonary disease (COPD), pulmonary fibrosis, idiopathic pulmonary fibrosis, radiation induced fibrosis, silicosis, asbestos induced pulmonary or pleural fibrosis, acute lung injury, acute respiratory distress syndrome (ARDS, including bacterial pneumonia induced, trauma induced, viral pneumonia induced, ventilator induced, non-pulmonary sepsis induced, and aspiration induced), usual interstitial pneumonia (UIP), cystic fibrosis, Chronic lymphocytic leukemia (CLL)-associated fibrosis, Hamman-Rich syndrome, Caplan syndrome, coal worker's pneumoconiosis, cryptogenic fibrosing alveolitis, obliterative bronchiolitis, chronic bronchitis, emphysema, Weg
  • the inhalable formulations described herein are used in the treatment of various fibroses associated with LPA-mediated or LPA-dependent aberrant wound healing and/or fibrosis in a mammal.
  • the inhalable formulations described herein are administered to the lungs of a mammal and antagonize LPA receptors in the lungs of the mammal.
  • antagonizing LPA receptors that are associated with aberrant wound healing and/or fibrosis reduces or inhihbits the proliferation of fibroblasts and/or increases apoptosis of fibroblasts associated with fibrotic disorders.
  • the inhalable formulations described herein reduce, ameliorate or inhibit aberrant wound healing, fibroblast proliferation and/or fibrosis associated with LPA-dependent or LPA-mediated fibrotic disorders.
  • the LPA receptors are LPAi and/or LP A3 receptors. In one aspect, the LPA receptors are LPAi and/or LPA2 receptors.
  • the inhalable formulations described herein are used in the treatment of lung diseases associated with fibrosis in a mammal. In one aspect, the inhalable formulations described herein are used in the treatment of pulmonary fibroses in a mammal.
  • the inhalable formulations described herein are used in the treatment of lung cancer, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), usual interstitial pneumonia (UIP), cystic fibrosis, Chronic lymphocytic leukemia (CLL)-associated fibrosis, Hamman-Rich syndrome, Caplan syndrome, coal worker's pneumoconiosis, silicosis, interstitial lung disease, asbestos induced pulmonary or pleural fibrosis, cryptogenic fibrosing alveolitis, or obliterative bronchiolitis in a mammal.
  • lung cancer pulmonary fibrosis
  • IPF idiopathic pulmonary fibrosis
  • UFP usual interstitial pneumonia
  • cystic fibrosis cystic fibrosis
  • CLL Chronic lymphocytic leukemia
  • Hamman-Rich syndrome Caplan syndrome
  • coal worker's pneumoconiosis silicosis
  • interstitial lung disease asbestos
  • the inhalable formulations described herein are adminstered to a mammal with pulmonary fibrosis or with a predisposition of developing pulmonary fibrosis in combination with one or more other agents that are used to treat fibrosis.
  • the one or more agents include corticosteroids.
  • the one or more agents include immunosuppresants.
  • the one or more agents include B-cell antagonists.
  • the one or more agents include uteroglobin.
  • a method of reducing lung injury, vascular leakage, inflammation and pulmonary fibrosis in a mammal comprising administering to the mammal an inhalable formulation that includes at least one LPA receptor antagonist.
  • a method of attenuating pulmonary fibrosis in a mammal comprising administering to the mammal an inhalable formulation that includes at least one LPA receptor antagonist.
  • provided is a method of attenuating tissue remodeling and fibrosis in the lungs of a mammal comprising administering to the mammal an inhalable formulation that includes at least one LPA receptor antagonist.
  • a method of decreasing cytokine production in a mammal comprising administering to the mammal an inhalable formulation that includes at least one LPA receptor antagonist.
  • the method of decreasing cytokine production in a mammal comprising administering to the mammal an inhalable formulation that includes at least one LPA receptor antagonist results in a reduction of tissue damage and fibrosis in the lungs of the mammal.
  • provided is a method of treating pulmonary fibrosis in a mammal comprising administering to the mammal an inhalable formulation that includes at least one LPA receptor antagonist.
  • a method of treating fibrosis in a mammal while maintaining body weight in the mammal comprising administering to the mammal an inhalable formulation that includes at least one LPA receptor antagonist.
  • a method of treating respiratory disease in a mammal comprising administering to the mammal an inhalable formulation that includes at least one LPA receptor antagonist.
  • a method of treating fibrosis in a mammal comprising administering to the mammal an inhalable formulation that includes at least one LPA receptor antagonist, wherein the fibrosis in the mammal is not responsive to treatment with pirfenidone.
  • a method of controlling an abnormal accumulation or activation of cells, fibronectin, collagen or increased fibroblast recruitment in lung tissues of a mammal comprising administering to the mammal an inhalable formulation that includes at least one LPA receptor antagonist.
  • the abnormal accumulation or activation of cells, fibronectin, collagen or increased fibroblast recruitment in the tissue results in pulmonary fibrosis.
  • LPA is a contributor to the pathogenesis of respiratory diseases.
  • the respiratory disease is asthma.
  • Proinflammatory effects of LPA include degranulation of mast cells, contraction of smooth-muscle cells and release of cytokines from dendritic cells.
  • Airway smooth muscle cells, epithelial cells and lung fibroblasts all show responses to LPA.
  • the release of LPA from platelets activated at a site of injury and its ability to promote fibroblast proliferation and contraction are features of LPA as a mediator of wound repair.
  • asthma is an inflammatory disease where inappropriate airway "repair" processes lead to structural "remodeling" of the airway.
  • the cells of the airway are subject to ongoing injury due to a variety of insults, including allergens, pollutants, other inhaled environmental agents, bacteria and viruses, leading to the chronic inflammation that characterizes asthma.
  • the release of normal repair mediators, including LPA is exaggerated or the actions of the repair mediators are inappropriately prolonged leading to inappropriate airway remodeling.
  • Major structural features of the remodeled airway observed in asthma include a thickened lamina reticularis (the basement membrane-like structure just beneath the airway epithelial cells), increased numbers and activation of myofibroblasts, thickening of the smooth muscle layer, increased numbers of mucus glands and mucus secretions, and alterations in the connective tissue and capillary bed throughout the airway wall.
  • LPA contributes to these structural changes in the airway.
  • LPA is involved in acute airway
  • LPA contributes to the long- term structural remodeling and the acute hyperresponsiveness of the asthmatic airway. In one aspect, LPA contributes to the hyper-responsiveness that is a primary feature of acute exacerbations of asthma.
  • the fibroblast proliferation and contraction and extracellular matrix secretion stimulated by LPA contributes to the fibroproliferative features of other airway diseases, such as the peribronchiolar fibrosis present in chronic bronchitis, emphysema, and interstitial lung disease.
  • Emphysema is also associated with a mild fibrosis of the alveolar wall, a feature which is believed to represent an attempt to repair alveolar damage.
  • LPA plays a role in the fibrotic interstitial lung diseases and obliterative bronchiolitis, where both collagen and myofibroblasts are increased.
  • LPA is involved in several of the various syndromes that constitute chronic obstructive pulmonary disease.
  • LPA administration of LPA in vivo induces airway hyper-responsiveness, itch-scratch responses, infiltration and activation of eosinophils and neutrophils, vascular remodeling, and nociceptive flexor responses.
  • LPA also induces histamine release from mast cells.
  • histamine induces various responses, such as contraction of smooth muscle, plasma exudation, and mucus production. Plasma exudation is important in the airway, because the leakage and subsequent airway-wall edema contribute to the development of airway hyperresponsiveness.
  • Plasma exudation progresses to conjunctival swelling in ocular allergic disorder and nasal blockage in allergic rhinitis (Hashimoto et ah, J Pharmacol Sci 100, 82 - 87, 2006).
  • plasma exudation induced by LPA is mediated by histamine release from mast cells via one or more LPA receptors.
  • the LPA receptor(s) include LPAi and/or LP A3.
  • respiratory disease refers to diseases affecting the organs that are involved in breathing, such as the nose, throat, larynx, eustachian tubes, trachea, bronchi, lungs, related muscles (e.g., diaphram and intercostals), and nerves.
  • Respiratory diseases include, but are not limited to, asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen- induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, child- onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, including chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation and cystic fibrosis, and hypoxia.
  • asthma refers to any disorder of the lungs characterized by variations in pulmonary gas flow associated with airway constriction of whatever cause (intrinsic, extrinsic, or both; allergic or non-allergic).
  • the term asthma may be used with one or more adjectives to indicate cause.
  • the inhalable formulations described herein are used in the treatment of various allergic disorders in a mammal.
  • the inhalable formulations described herein are administered to the lungs of a mammal and antagonize LPA receptors.
  • antagonizing LPA receptors associated with airway remodeling reduces or inhihbits the proliferation of fibroblasts and/or increases apoptosis of fibroblasts associated with airway remodeling that is associated with allergic disorders.
  • the inhalable formulations described herein reduce, ameliorate or inhibit inflammation, airway remodeling and/or fibrosis associated with LPA- dependent or LPA-mediated allergic disorders.
  • the LPA receptors are LPAi and/or LPA 3 receptors.
  • the inhalable formulations described herein are used in the treatment of respiratory diseases, disorders or conditions in a mammal. In one aspect, the inhalable formulations described herein are used in the treatment of asthma in a mammal. In one aspect, the inhalable formulations described herein are used in the treatment of chronic asthma in a mammal. In some instances, the inhalable formulations described herein are used in the treatment of acute respiratory distress syndrome (ARDS, including bacterial pneumonia induced, trauma induced, viral pneumonia induced, ventilator induced, non-pulmonary sepsis induced, and aspiration induced) in a mammal.
  • ARDS acute respiratory distress syndrome
  • Chronic obstructive pulmonary disease includes, but is not limited to, chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation, and cystic fibrosis.
  • Lysophospholipid receptor signaling plays a role in the etiology of cancer.
  • Lysophosphatidic acid (LPA) and its G protein-coupled receptors (GPCRs) LPA l5 LPA 2 , and/or LPA 3 play a role in the development of several types of cancers.
  • the initiation, progression and metastasis of cancer involve several concurrent and sequential processes including cell proliferation and growth, survival and anti- apoptosis, migration of cells, penetration of foreign cells into defined cellular layers and/or organs, and promotion of angiogenesis.
  • CLL Chronic Lymphocytic Leukemia
  • B-cells LPA acts as a growth factor promoting cell proliferation.
  • LPA also contributes to VEGF production in B cell malignancies leading to cell survival.
  • LPA protects epithelial and fibroblast cell lines from apoptosis.
  • LPAi expression is increased in primary CLL cells compared with normal B-cells (J. Biol. Chem. 2005, 280, 9498-9508).
  • Treatment of primary CLL cells with an LPA receptor antagonist reverses the protective effect of LPA against apoptosis and provides effective therapy against B-cell derived malignancies such as CLL.
  • the inhalable formulations described herein are used in the treatment of lung cancer and/or fibrosis associated with lung cancer. In one aspect, the inhalable formulations described herein are used in the treatment of lung cancer. In one aspect, the inhalable formulations described herein are administered to the lungs of a mammal and antagonize LPA receptors associated with cell proliferation. In some instances, antagonizing LPA receptors associated with cell proliferation reduces or inhibits the proliferation of fibroblasts and/or B-cells and/or increases apoptosis of fibroblasts and/or B-cells associated with lung cancer and/or fibrosis associated with lung cancer. In one aspect the inhalable formulations described herein reduce, ameliorate or inhibit cell proliferation and/or fibrosis associated with LPA-dependent or LPA-mediated cancers. In one aspect, the LPA receptors are LPAi and/or LPA 3 receptors.
  • cancer refers to an abnormal growth of cells which tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread).
  • the type of cancer includes, but is not limited to, solid tumors, melanoma or basal cell cancer or hematological tumors (such as the leukemias) at any stage of the disease with or without metastases.
  • the lung cancer is non-small cell lung cancer.
  • the lung cancer is an adenocarcinoma.
  • the inhalable formulations described herein are used in the treatment of B-cell derived malignancies (e.g., CLL) and/or CLL-associated fibrosis.
  • LPA has been shown to regulate immunological responses by modulating activities/functions of immune cells such as T-/B-lymphocytes and macrophages.
  • LPA activates IL-2 production/cell proliferation through LPAi.
  • Expression of LPA-induced inflammatory response genes is mediated by LPAi and LPA 3 .
  • LPA modulates the chemotaxis of inflammatory cells.
  • the proliferation and cytokine-secreting activity in response to LPA of immune cells, platelet aggregation activity in response to LPA, acceleration of migration activity in monocytes, activation of NF-KB in fibroblast, enhancement of fibronectin-binding to the cell surface, and the like are known.
  • LPA is associated with various inflammatory/immune diseases .
  • an inhalable formulation that includes at least one LPA receptor antagonist is used to treat or prevent inflammation in a mammal. In one aspect, an inhalable formulation that includes at least one LPA receptor antagonist is used to treat or prevent inflammation of the lungs in a mammal. In one aspect, an inhalable formulation that includes at least one LPA receptor antagonist finds use in the treatment or prevention of inflammatory/immune disorders that affect lung tissues in a mammal.
  • inflammatory/immune disorders include, but are not limited to, asthma, allergic rhinitis, pulmonary fibrosis, cystic fibrosis.
  • the subject already has a LPA-dependent or LPA-mediated disease or condition of the lung at the time of administration, or is at risk of developing a LPA-dependent or LPA-mediated disease or condition of the lung.
  • kits for preventing or treating eosinophil and/or basophil and/or dendritic cell and/or neutrophil and/or monocyte and/or T-cell recruitment comprising administering at least once to the mammal an inhalable formulation that includes at least one LPA receptor antagonist.
  • methods described herein include the diagnosis or
  • the activity of LPAi in a mammal is directly or indirectly modulated by the administration of (at least once) an inhalable formulation that includes at least one LPA receptor antagonist.
  • modulation includes, but is not limited to, reducing and/or inhibiting the activity of LPAi.
  • the activity of LPA in a mammal is directly or indirectly modulated, including reducing and/or inhibiting, by the administration of (at least once) a therapeutically effective amount of an inhalable formulation described herein.
  • modulation includes, but is not limited to, reducing and/or inhibiting the activity of an LPA receptor.
  • the LPA receptors are LPAi and/or LPA 3 receptors.
  • the LPA receptors are LPAi and/or LPA 2 receptors.
  • Also provided is a method of inhibiting the physiological activity of LPA in a mammal comprising administering to the mammal an inhalable formulation that includes at least one LPA receptor antagonist.
  • a medicament for treating a LPA-dependent or LPA-mediated disease or condition in a mammal comprising a therapeutically effective amount of an LPA antagonist.
  • an inhalable formulation that includes at least one LPA receptor antagonist in the treatment or prevention of a LPA-dependent or LPA-mediated disease or condition.
  • a method for treating or preventing a LPA-dependent or LPA-mediated disease or condition in a mammal comprising administering administering to the mammal an inhalable formulation that includes at least one LPA receptor antagonist.
  • LPA-dependent or LPA-mediated diseases or conditions include, but are not limited to, fibrosis involving the lungs, cancer involving the lungs, cardiovascular disease, respiratory diseases or conditions, inflammatory disease.
  • the LPA-dependent or LPA-mediated disease or condition is a respiratory disease or condition.
  • the respiratory disease or condition is asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pulmonary arterial hypertension or acute respiratory distress syndrome.
  • COPD chronic obstructive pulmonary disease
  • pulmonary fibrosis pulmonary arterial hypertension or acute respiratory distress syndrome.
  • the LPA-dependent or LPA-mediated disease or condition is selected from idiopathic pulmonary fibrosis; other diffuse parenchymal lung diseases of different etiologies including iatrogenic drug-induced fibrosis, occupational and/or environmental induced fibrosis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonia), collagen vascular disease, alveolar proteinosis, langerhans cell granulomatosis, lymphangioleiomyomatosis, inherited diseases
  • the LPA-dependent or LPA-mediated disease or condition is described herein.
  • a method of improving lung function in a mammal comprising administering to the mammal an inhalable formulation that includes at least one LPA receptor antagonist.
  • the mammal has been diagnosed as having lung fibrosis.
  • inhalable formulations that includes at least one LPA receptor antagonist are used to treat idiopathic pulmonary fibrosis (usual interstitial pneumonia) in a mammal.
  • inhalable formulations that includes at least one LPA receptor antagonist are used to treat post-transplant fibrosis associated with chronic rejection in a mammal: Bronchiolitis obliterans for lung transplant.
  • inhalable formulations that includes at least one LPA receptor antagonist are used for inhibiting the activity of at least one LPA receptor in the lungs of a mammal or for the treatment of a disease or condition affecting the pulmonary system (i.e. lungs) that would benefit from inhibition of the activity of at least one LPA receptor in the lungs of the lungs of the mammal.
  • the LPA receptor is LPAi.
  • an LPA receptor antagonist is selected from LPA receptor antagonists described herein or known in the art.
  • the LPA receptor antagonist is an LPAi selective antagonist.
  • the LPA antagonist is an LPAi and LPA 3 dual antagonist.
  • the LPA antagonist is an LPAi and LPA 2 dual antagonist.
  • the activity of LPA in a mammal is directly or indirectly modulated by the administration of (at least once) a therapeutically effective amount of an LPA receptor antagonist.
  • modulation includes, but is not limited to, reducing and/or inhibiting the activity of LPAi.
  • the activity of LPA in a mammal is directly or indirectly modulated, including reducing and/or inhibiting, by the administration of (at least once) a therapeutically effective amount of an LPA receptor antagonist.
  • modulation includes, but is not limited to, reducing and/or inhibiting the activity of an LPA receptor.
  • the LPA receptors are LPAi and/or LP A3 receptors.
  • the LPA receptors are LPAi and/or LPA 2 receptors.
  • LPA receptor antagonists are disclosed herein or in any one of the following: US Provisional Application no. 61/122,568; US Provisional Application no. 61/183,785; US Patent Application no. 12/638,702; US Provisional Application no. 61/121,862; US Provisional Application no. 61/231,282; US Provisional Application no. 61/247,681; US Provisional Application no. 61/2472877;
  • the LPA receptor antagonist has the structure of Formula (I):
  • Pv 1 is -C0 2 H, -C0 2 R D , tetrazolyl, 5-oxo-2,5-dihydro-[l,2,4]oxadiazol-3-yl, -
  • R D is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , - CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , or -C(CH 3 ) 3 ;
  • L 1 is Ci-C 4 alkylene or C 3 -C6cycloalkylene
  • Pv 3 is H, -CH 3 , -CH 2 CH 3 , or -CF 3 ;
  • Ci-C6alkyl substituted or unsubstituted C 3 -C6cycloalkyl, or substituted or
  • R c is independently F, CI, Br, I, -OH, -CN, d-C 4 alkyl, Ci-C 4 fluoroalkyl, C
  • CY is substituted or unsubstituted phenyl; wherein if CY is substituted then CY is substituted with 1 or 2 R c ; each R c is independently F, CI, -CN, -CH 3 , -CF 3 , -OH, -OCF 3 ,
  • CY is ; n is 0, 1, or 2. In some embodiments, n is 0 or
  • CY is cyclopropyl, cyclobutyl, cyclopentyl, cyclopent-l-enyl, 2- chlorocyclopent-l-enyl, cyclohexyl, cyclohex- 1 -enyl, 2-chlorocyclohex-l-enyl, phenyl, 2- fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2- chlorophenyl, 2,6-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 2,4-dichlorophenyl, 2- hydroxyphenyl, 3-hydroxyphenyl, 4- hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4- methoxyphenyl, 2-trifluoromethylphenyl, 3-trifluoro
  • CY is phenyl, 2-fluorophenyl, 2- chlorophenyl, 2-trifluoromethylphenyl, or 2-methylphenyl. In some embodiments, CY is phenyl, 2- fluorophenyl, or 2-chlorophenyl. In some embodiments, CY is phenyl.
  • the compound of Formula (I) has the following structure:
  • the LPA receptor antagonist has the structure of Formula (II):
  • R 1 is -CO2H.
  • L 1 is -CH 2 -, -CH 2 CH 2 -, - CH 2 CH 2 CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH(CH 2 CH 3 )-, -C(CH 2 CH 3 ) 2 -, -CH 2 CH(CH 3 )-, -CH 2 C(CH 3 ) 2 - , cyclopropyl- 1,1 -diyl, cyclopropyl- 1,2-diyl, cyclobutyl- 1,1 -diyl, cyclopentyl- 1,1 -diyl or cyclohexyl - 1,1 -diyl.
  • L 1 is -CH 2 -, -C(CH 3 ) 2 -, or -C(CH 2 CH 3 ) 2 -. In some embodiments, L is -CH 2 - or cyclopropyl- 1 , 1 -diyl. In some embodiments, L 1 is -CH 2 -. In some embodiments, L 1 is cyclopropyl- 1 , 1 -diyl, cyclobutyl- 1 , 1 -diyl, cyclopentyl- 1 , 1 -diyl or cyclohexyl- 1 , 1 -diyl.
  • L 1 is cyclopropyl- 1 , 1 -diyl.
  • R 3 is H.
  • R 3 is -CH 3 .
  • each of R c is independently selected from F, CI, -CH 3 , and -CF 3 ; n is 0 or 1.
  • the LPA receptor antagonist is selected from:
  • the LPA receptor antagonist has structure of Formula (III):
  • R D is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -
  • L 1 is absent, or a Ci-C 6 alkylene
  • R 3 is H, -CH 3 , -CH 2 CH 3 , or -CF 3 ;
  • R 8 is H, or -CH 3 ;
  • CY is substituted or unsubstituted phenyl; wherein if CY is substituted then CY is
  • each R c is independently F, CI, Br, I, -OH, -CN, C
  • Ci-C 4 fluoroalkyl Ci-C 4 fluoroalkoxy, or C C 4 alkoxy;
  • R 1 is -C0 2 H or -C0 2 R D . In some embodiments, R 1 is -C0 2 H. In some embodiments, L 1 is -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH 2 CH(CH 3 )-, -CH 2 C(CH 3 ) 2 -, -
  • L 1 is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 -.
  • L 1 is -CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 -.
  • L 1 is -CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 -.
  • R 3 is H.
  • R 3 is -CH 3 .
  • R 8 is -CH 3 .
  • each of R c is independently selected from F, CI, -CH 3 , and -CF 3 .
  • R 4 is
  • CY is a substituted or unsubstituted phenyl, wherein if CY is substituted then CY is substituted with 1 or 2 R c ; each R c is independently F, CI, -CN, -CH 3 , -CF 3 , - OH, -OCF 3 , or -OCH 3 .
  • the LPAl antagonist is selected from: 6-(4- ⁇ 4-[l-(2-Chloro-phenyl)- ethoxycarbonylamino]-3-methyl-isoxazol-5-yl ⁇ -phenyl)-hex-5-ynoic acid, 7-(4- ⁇ 4-[l-(2-chloro- phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl ⁇ -phenyl)-hept-6-ynoic acid, or a
  • the LPA receptor antagonist has the structure of Formula (IV):
  • A is an aryl or heteroaryl ring
  • R 3 is H, Ci-C 4 alkyl, Ci-C 4 fluoroalkyl
  • R 8 is H, C C 4 alkyl, C C 4 fluoroalkyl
  • CY is a substituted or unsubstituted C3-C 6 cycloalkyl, a substituted or unsubstituted
  • each R c is independently selected from F, CI, Br, I, -CN, -OH, C C 4 alkyl, Ci-C 4 fluoroalkyl, Ci-C 4 fluoroalkoxy, C C 4 alkoxy, and Ci-C 4 heteroalkyl;
  • R 5 and R 6 are each independently selected from H, halogen, -CN, -N0 2 , -OH, -OR 10 , C
  • Ci-C 4 fluoroalkyl Ci-C 4 fluoroalkoxy, Ci-C 4 alkoxy, and Ci-C 4 heteroalkyl
  • R 10 is selected from Ci-C 6 alkyl, Ci-C 6 heteroalkyl, Ci-C 6 fluoroalkyl, a substituted or
  • A is phenyl, or a 5- or 6-membered monocyclic heteroaryl.
  • A is a phenyl, pyridinyl, thiazolyl, or pyrimidinyl.
  • R 5 and R 6 are each independently selected from hydrogen, halogen, or hydroxy.
  • R 3 is methyl, ethyl, isopropyl or trifluoromethyl. In some embodiments, R 3 is methyl.
  • CY is a substituted or unsubstituted CYcycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; or
  • the LPA1 antagonist has one of the following structures:
  • the LPA receptor antagonist has the structure of Formula (V):
  • A is an aryl or heteroaryl ring
  • B is an aryl or heteroaryl ring
  • L is absent, C C 4 alkylene, C C 4 heteroalkylene, -0-, -S-, -SO-, -S0 2 -, -NH-, -NR 2 -, or -
  • R 2 is CrQalkyl
  • R 3 is H, C C 4 alkyl, or Ci-C 4 fluoroalkyl
  • R 8 is H, C C 4 alkyl, or C C 4 fiuoroalkyl
  • CY is a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; wherein if CY is substituted then CY is substituted with 1 or 2 R c ; each R c is independently selected from F, CI, Br, I, -CN, -OH, C C 4 alkyl, C C 4 fluoroalkyl, Ci-C 4 fluoroalkoxy, Ci-C 4 alkoxy, and Ci-C 4 heteroalkyl; R 5 and R 6 are each independently selected from H, halogen, -CN, -N0 2 , -OH, -OR 10 , C
  • Ci-C 4 fluoroalkyl Ci-C 4 fluoroalkoxy, Ci-C 4 alkoxy, and Ci-C 4 heteroalkyl
  • R 5a and R 6a are each independently selected from H, halogen, -CN, -N0 2 , -OH, -OR 10 , -
  • Ci-C 4 alkyl substituted or unsubstituted Ci-C 4 alkyl, Ci-C 4 fluoroalkyl, Ci-C 4 fluoroalkoxy,
  • R is selected from Ci-C 6 alkyl, Ci-C 6 heteroalkyl, Ci-C 6 fluoroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl;
  • rin A is a substituted or unsubstituted monocyclic ring wherein the
  • rin A is a substituted or unsubstituted monocyclic ring wherein the
  • A is a phenyl ring. In some embodiments, A is a monocyclic heteroaryl. In some embodiments, A is a 6-membered monocyclic heteroaryl. In some
  • A is a pyridinyl ring.
  • L is absent and A-L-B is biphenyl.
  • B is a phenyl ring.
  • B is a monocyclic heteroaryl.
  • B is a 6-membered monocyclic heteroaryl.
  • B is a pyridinyl ring.
  • A-L-B is phenyl-pyridyl.
  • R 5 and R 6 are each independently selected from hydrogen, halogen, or hydroxy.
  • R 5a and R 6a are each independently selected from hydrogen, halogen, hydroxy, hydroxymethyl or substituted or unsubstituted heterocycloalkyl.
  • R 3 is methyl, ethyl, isopropyl or
  • L is absent, -CH 2 -, -CH 2 0-, -OCH 2 -, -CH 2 S-, -SCH 2 -, -CH 2 NH-, - NHCH 2 -, -0-, -S-, or -NH-. In some embodiments, L 2 is absent.
  • the LPA1 antagonist has a structure selected from:
  • the LPA receptor antagonist has the structure of Formula (VI) or a pharmaceutically acceptable salt thereof:
  • R D is H or Ci-C 6 alkyl
  • R E is Ci-C 6 alkyl, C3-C 6 cycloalkyl, or substituted or unsubstituted phenyl;
  • L 3 is a substituted or unsubstituted C 3 -C 6 alkylene, a substituted or unsubstituted C 3 - C 6 fluoroalkylene, or a substituted or unsubstituted C3-C 6 heteroalkylene, where if L 3 is substituted then L 3 is substituted with 1, 2 or 3 R 13 ; each R 13 is independently F, C C 4 alkyl, Ci-C 4 fluoroalkyl, or -OH;
  • each R c is independently halogen, -CN, -N0 2 , -OH, Ci-C 4 alkyl, Ci-C 4 fluoroalkyl, Ci- C 4 fluoroalkoxy, C C 4 alkoxy, or Ci-C 4 heteroalkyl;
  • R 3 is H or C C 4 alkyl
  • n 0, 1, or 2.
  • R 1 is -C0 2 R D
  • R 1 is -C0 2 H.
  • R E is Ci-C 6 alkyl.
  • R E is -CH 3 or - CH 2 CH 3 .
  • R E is -CH 3 .
  • R D is H, -CH 3 or -CH 2 CH 3 .
  • R D is -CH 2 CH 3 .
  • R D is H.
  • each R c is independently halogen, -CN, -OH, -CH 3 , -CH 2 CH 3 , - CH(CH 3 ) 2 , -CF 3 , -OCF 3 , -OCH 3 or -OCH 2 CH 3 .
  • n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.
  • 2-fluorophenyl 2,3-difluoropheny
  • 2-methylphenyl In some embodiments, is phenyl, 2-fluorophenyl, or 2-chlorophenyl.
  • R 3 is phenyl.
  • R 3 is -H, -CH 3 or -CH 2 CH 3 . In some embodiments, R 3 is -CH 3 or - CH 2 CH 3 . In some embodiments, R 3 is -CH 3 .
  • R D is H or C C 4 alkyl;
  • R E is C Qalkyl;
  • R 3 is -H, -CH 3 or -CH 2 CH 3 .
  • L 3 is a substituted or unsubstituted C 3 -C 4 alkylene, a substituted or unsubstituted C 3 -C 4 fluoroalkylene, or a substituted or unsubstituted C 3 -C 6 heteroalkylene; where if L 3 is substituted then L 3 is substituted with 1, 2 or 3 R 13 ; each R 13 is independently F, -CH 3 , -CH 2 CH 3 , - CF 3 , or -OH.
  • L 3 is a substituted or unsubstituted butylene, a substituted or unsubstituted fiuorobutylene, or a substituted or unsubstituted difiuorobutylene; where if L 3 is substituted then L 3 is substituted with 1 or 2 R 13 .
  • L 3 is a substituted or unsubstituted C 3 -C 6 heteroalkylene; where if L 3 is substituted then L 3 is substituted with 1 or 2 R 13 .
  • L 3 is -(substituted or unsubstituted C 3 -C 4 alkylene)-0-, -(substituted or unsubstituted Ci-C 3 alkylene)-0-(substituted or unsubstituted Ci-C 3 alkylene)-, -0-(substituted or unsubstituted C 3 -C 4 alkylene)-, -(substituted or unsubstituted C 3 -C 4 alkylene)-S-, -(substituted or unsubstituted Ci-C 3 alkylene)-S-(substituted or unsubstituted Ci-C 3 alkylene)-, -S-(substituted or unsubstituted C 3 -C 4 alkylene)-, -(substituted or unsubstituted C 3 -C 4 alkylene)-NH-, -(
  • L 3 is -NH-(substituted or unsubstituted C 3 -C 4 alkylene); where if L 3 is substituted then L 3 is substituted with R 13 .
  • L 3 is -(substituted or unsubstituted Ci-C 3 alkylene)-0-(substituted or unsubstituted Ci-C 3 alkylene)-, or -(substituted or unsubstituted Ci-C 3 alkylene)-S-(substituted or unsubstituted Ci-C 3 alkylene)-; where if L 3 is substituted then L 3 is substituted with R 13 .
  • L 3 is -(substituted or unsubstituted ethylene)-0-(substituted or unsubstituted methylene)-, or -(substituted or unsubstituted ethylene)-S-(substituted or unsubstituted methylene)-; where if L 3 is substituted then L 3 is substituted with R 13 .
  • L 3 is a substituted or unsubstituted C 3 -C 4 alkylene, a substituted or unsubstituted C 3 -C 4 fluoroalkylene, or a substituted or unsubstituted C 3 -C 6 heteroalkylene.
  • L 3 is a substituted or unsubstituted butylene, a substituted or unsubstituted fiuorobutylene, or a substituted or unsubstituted difiuorobutylene.
  • L 3 is a substituted or unsubstituted C 3 -C 6 heteroalkylene. In some embodiments, L 3 is a substituted or unsubstituted C 3 -C 4 heteroalkylene.
  • L 3 is -NH-(substituted or unsubstituted C 3 -C 4 alkylene). [00134] In some embodiments, L 3 is -(substituted or unsubstituted Ci-C 3 alkylene)-0-(substituted or unsubstituted Ci-C 3 alkylene)-, or -(substituted or unsubstituted Ci-C 3 alkylene)-S-(substituted or unsubstituted Ci-C 3 alkylene)-.
  • L 3 is -(substituted or unsubstituted ethylene)- 0-(substituted or unsubstituted methylene)-, or -(substituted or unsubstituted ethylene)-S-(substituted or unsubstituted methylene)-.
  • L 3 is substituted with 1, 2 or 3 R 13 . In some embodiments, L 3 is substituted with 1 or 2 R 13 . In some embodiments, L 3 is substituted with R 13 . In some embodiments, L 3 is unsubstituted. In some embodiments, if L 3 is substituted then L 3 is substituted with 1, 2 or 3 R 13 . In some embodiments, if L 3 is substituted then L 3 is substituted with 1 or 2 R 13 . In some
  • each R 13 is independently F, Ci-C 4 alkyl, Ci-C 4 fiuoroaikyl, or - OH. In some embodiments, each R 13 is independently F, Ci-C 4 alkyl, or -OH. In some embodiments, each R 13 is independently Ci-C 4 alkyl, or -OH. In some embodiments, each R 13 is independently F, - CH 3 , -CH 2 CH 3 , -CF 3 , or -OH. In some embodiments, each R 13 is independently F, -CH 3 , or -OH.
  • each R 13 is independently -CH 3 , or -OH.
  • R 13 is F, -CH 3 , - CH 2 CH 3 , -CF 3 , or -OH.
  • R 13 is F, -CH 3 , -CH 2 CH 3 , or -OH.
  • R 13 is -CH 3 or -OH.
  • R 13 is Ci-C 4 alkyl, or -OH.
  • the LPA receptor antagonist has the structure of Formula (VII) or a pharmaceutically acceptable salt thereof:
  • R D is H or C C 6 alkyl
  • R E is C1-C6 alkyl or a substituted or unsubstituted phenyl
  • ring A is a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic Ci-C 5 heteroarylene, where if ring A is substituted, then ring A is substituted with 1 or 2 R 14 , each R 14 is independently selected from halogen, -CN, -OH, Ci-C 4 alkyl, C
  • L 4 is absent, or a substituted or unsubstituted C 1 -C 4 alkylene, where if L 4 is substituted then
  • L 4 is substituted with R 13 , where R 13 is F, C C 4 alkyl, -OH, or -OR D ;
  • R 3 is H or Ci-C 4 alkyl
  • each R c is independently selected from halogen, -CN, -OH, Ci-C 4 alkyl, Ci-C 4 fluoroalkyl, C
  • n 0, 1 or 2.
  • substituents are selected from among from a subset of the listed alternatives.
  • R 1 is -CO 2 R 13 .
  • R 1 is -CO 2 H.
  • R E is Ci-C 6 alkyl.
  • R E is -CH 3 or - CH 2 CH 3 .
  • R D is H, -CH 3 or -CH 2 CH 3 .
  • R D is H.
  • R 3 is Ci-C 4 alkyl. In some embodiments, R 3 is H, -CH 3 , or - CH 2 CH 3 . In some embodiments, R 3 is -CH 3 , or -CH 2 CH 3 . In some embodiments, R 3 is -CH 3 . In some embodiments, R 3 is H.
  • L 2 is -N(R D )-, substituted or unsubstituted C 1 -C 2 alkylene, or substituted or unsubstituted Ci-C 2 heteroalkylene, where if L 2 is substituted, then L 2 is substituted with R 12 .
  • L 2 is -N(H)-, -N(CH 3 )-, substituted or unsubstituted methylene, or substituted or unsubstituted ethylene, where if L 2 is substituted, then L 2 is substituted with R 12 . In some embodiments, L 2 is -N(H)-. In some embodiments, L 2 is substituted or
  • L 2 is -NH-, -N(CH 3 )-, -CH 2 -, -CH(CH 3 )-, -CH(OH)-, -CH(OR D )-, -CH 2 NH-, - CH(CH 3 )NH-, -NHCH 2 - or -NHCH(CH 3 )-.
  • L 2 is -NH-, -N(CH 3 )-, -CH 2 NH-, - CH(CH 3 )NH-, -NHCH 2 - or -NHCH(CH 3 )-.
  • L 2 is -NH-.
  • L 2 is -CH 2 -, -CH(CH 3 )-, -CH(OH)-, -CH(OR D )-, -CH 2 NH-, -CH(CH 3 )NH-, -NHCH 2 - or - NHCH(CH 3 )-.
  • L 2 is -CH 2 -, -CH(CH 3 )-, -CH(OH)-, or -CH(OR D )-.
  • L 2 is -CH 2 - or -CH(OH)-.
  • L 2 is -CH(OH)-.
  • L 2 is -CH 2 -.
  • R 12 is F, -CH 3 , -CH 2 CH 3 , -OH, -OCH 3 , or -OCH 2 CH 3 . In some embodiments, R 12 is -CH 3 , or -OH.
  • L 4 is absent, -CH 2 -, -CH(CH 3 )-, -CH(OH)-, -CH 2 CH 2
  • each R c is halogen, -OH, -CH 3 , -CH 2 CH 3 , -CF 3 , -OCF 3 , -OCH 3 , - OCH 2 CH 3 , -CH 2 OCH 3 , -CH 2 OCH 2 CH 3 , or -CH 2 N( CH 3 ) 2 .
  • each R c is independently selected from halogen, -OH, -CH 3 , -CH 2 CH 3 , -CF 3 , -OCF 3 , -OCH 3 and -OCH 2 CH 3 .
  • ring A is a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic Ci-C 5 heteroarylene, where if ring A is substituted, then ring A is substituted with 1 or 2 R 14 .
  • ring A is a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic Ci-Csheteroarylene containing 1-4 N atoms, 0 or 1 O atoms and 0 or 1 S atoms, where if ring A is substituted, then ring A is substituted with 1 or 2 R 14 .
  • ring A is a substituted or unsubstituted monocyclic Cr
  • ring A is a substituted or unsubstituted 5-membered monocyclic C C 4 heteroarylene containing 1-4 N atoms, 0 or 1 O atoms and 0 or 1 S atoms, where if ring A is substituted, then ring A is substituted with 1 or 2 R 14 .
  • ring A is a substituted or unsubstituted 6-membered monocyclic C 3 - Csheteroarylene containing 1-3 N atoms, where if ring A is substituted, then ring A is substituted with 1 or 2 R 14 .
  • ring A is a substituted or unsubstituted monocyclic ring wherein the groups -L 2 - and -L 4 - are in a 1 ,2-relationship on ring A (i.e. an ortho relationship). In some embodiments, ring A is a substituted or unsubstituted monocyclic ring wherein the groups -L 2 - and - L 4 - are in a 1,3 -relationship on ring A (i.e. a meta relationship).
  • ring A is a substituted or unsubstituted monocyclic ring wherein the groups -L 2 - and -L 4 - are in a 1 ,4- relationship on ring A (i.e. a para relationship).
  • ring A is unsubstituted or monosubstituted with R 14 . In some embodiments, ring A is unsubstituted. In some embodiments, ring A is monosubstituted with R 14 .
  • L 4 is absent, or a substituted or unsubstituted methylene, or substituted or unsubstituted ethylene, where if L 4 is substituted, then L 4 is substituted with R 13 . In some embodiments, L 4 is absent. In some embodiments, L 4 is a substituted or unsubstituted methylene, where if L 4 is substituted, then L 4 is substituted with R 13 . In some embodiments, L 4 is a substituted or unsubstituted ethylene, where if L 4 is substituted, then L 4 is substituted with R 13 . In some embodiments, L 4 is a substituted or unsubstituted ethylene, where if L 4 is substituted, then L 4 is substituted with R 13 .
  • R 13 is F, -CH 3 , -CH 2 CH 3 , -OH, -OCH 3 , or -OCH 2 CH 3 . In some embodiments, R 13 is -CH 3 .
  • L 4 is absent, -CH 2 -, or -CH(CH 3 )-.
  • L 2 is -NH-, -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )-, -CH 2 CH(CH 3 )-, - CH(CH 3 )CH 2 -, -CH(OH)-, -CH 2 CH(OH)-, -CH(OH)CH 2 -, -CH 2 NH-, -CH(CH 3 )NH-, -NHCH 2 - or - NHCH(CH 3 )-;
  • ring A is a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic Ci-Csheteroarylene containing 1-4 N atoms, 0 or 1 O atoms and 0 or 1 S atoms, where if ring A is substituted, then ring A is substituted with 1 or 2 R 14 ;
  • L 4 is absent, -CH 2 -, or -CH(CH 3 )-;
  • ring A is a substituted or unsubstituted phenyl, where if ring A is substituted, then ring A is substituted with 1 or 2 R 14 .
  • ring A is a substituted or unsubstituted monocyclic C
  • ring A is a substituted or unsubstituted 5-membered monocyclic C C 4 heteroarylene containing 1-4 N atoms, 0 or 1 O atoms and 0 or 1 S atoms, where if ring A is substituted, then ring A is substituted with 1 or 2 R 14 .
  • ring A is a substituted or unsubstituted furanyl, a substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted oxadiazolyl, or substituted or unsubstituted thiadiazolyl, where if ring A is substituted, then ring A is substituted with 1 or 2 R 14 .
  • each R 14 is independently selected from halogen, -CN, -OH, -CH 3 , - CH 2 CH 3 , -CF 3 , -OCF 3 , -OCH 3 and -OCH 2 CH 3 .
  • each R 14 is halogen, -CN, - OH, -CH 3 , -CH 2 CH 3 , -CF 3 , -OCF 3 , -OCH 3 or -OCH 2 CH 3 .
  • each R 14 is independently selected from halogen, -OH, and -CH 3 . .
  • R 14 is halogen, -OH, or -CH 3 .
  • each R 14 is independently selected from halogen and -CH 3 .
  • ring A is a substituted or unsubstituted 6-membered monocyclic C3- C 5 heteroarylene containing 1-3 N atoms, where if ring A is substituted, then ring A is substituted with l or 2 R 14 .
  • ring A is a substituted or unsubstituted pyridinylene, a substituted or unsubstituted pyridazinylene, a substituted or unsubstituted pyrimidinylene, a substituted or unsubstituted pyrazinylene, or a substituted or unsubstituted triazinylene, where if ring A is substituted, then ring A is substituted with 1 or 2 R 14 .
  • ring A is a substituted or unsubstituted pyridinylene, where if ring A is substituted, then ring A is substituted with 1 or 2 R 14 .
  • ring A is *0* , f , , ;
  • R D is H or C C 4 alkyl;
  • R E is Ci-C 4 alkyl;
  • L 2 is -CH 2 -, -CH(CH 3 )-, or -CH(OH)-;
  • ring A is a substituted or unsubstituted 5- membered monocyclic Ci-C 4 heteroarylene containing 1-4 N atoms, 0 or 1 O atoms and 0 or 1 S atoms, where if ring A is substituted, then ring A is substituted with R 14 ;
  • L 4 is -CH 2 - or -CH(CH 3 )-;
  • p is 0 or 1.
  • R D is H or C C 4 alkyl;
  • R E is Ci-C 4 alkyl;
  • L 2 is -CH 2 -, -CH(CH 3 )-, or -CH(OH)-;
  • ring A is a substituted or unsubstituted 5- membered monocyclic Ci-C 4 heteroarylene containing 1-4 N atoms and 0 or 1 O atoms, where if ring A is substituted, then ring A is substituted with R 14 , R 14 is halogen, -CN, -OH, -CH 3 , -CH 2 CH 3 , -CF 3 , -OCF 3 , -OCH 3 or -OCH 2 CH 3 ;
  • L 4 is -CH 2 - or -CH(CH 3 )-;
  • n is 0 or 1.
  • R D is H or C C 4 alkyl;
  • R E is C C 4 alkyl;
  • L 2 is -NH-, -CH 2 -, -CH(CH 3 )-, -CH(OH)-, -NHCH 2 - or -NHCH(CH 3 )-;
  • ring A is a substituted or unsubstituted 6-membered monocyclic C 3 -C 5 heteroarylene containing 1-3 N atoms, where if ring A is substituted, then ring A is substituted with R 14 ;
  • L 4 is absent, -CH 2 -, or -CH(CH 3 )-;
  • p is 0 or 1.
  • R D is H or C C 4 alkyl;
  • R E is C C 4 alkyl;
  • L 2 is -NH-, -CH 2 -, -CH(CH 3 )-, -CH(OH)-, -NHCH 2 - or -NHCH(CH 3 )-;
  • ring A is a substituted or unsubstituted pyridinylene, where if ring A is substituted, then ring A is substituted with R 14 , R 14 is halogen, -CN, -OH, -CH 3 , -CH 2 CH 3 , -CF 3 , -OCF 3 , -OCH 3 or -OCH 2 CH 3 ;
  • L 4 is absent, -CH 2 -, or -CH(CH 3 )-;
  • n is 0 or 1.
  • n is 0, 1 or 2. In some embodiments, n is 0 or 1. In some
  • n is 0. In some embodiments, n is 1. [00171] In some embodiments, *-G ( R c )n is phenyl, 2-fluorophenyl, 2,3-difluorophenyl, 2,4- difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 2- bromophenyl, 3-bromophenyl, 2,4-dichlorophenyl, 2-hydroxyphenyl, 3- hydroxyphenyl, 4- hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-trifluoromethylphenyl, 3- trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-fluoro-4-methoxyphenyl, 2-methylphenyl, 3- methylphenyl, 4-methylphenyl, 2-cyanophenyl,
  • the LPA receptor antagonist is selected from compounds (or a pharmaceutically acceptable salt, prodrug, active metabolite, or a pharmaceutically acceptable solvate thereof) described in U.S. Patent Nos. 6,964,975; 7,288,558 and U.S. Application Publication No. 2006/0194850, each of which is herein incorporated by reference.
  • the LPA receptor antagonist is 3-[[[4-[4-[[[[l-(2- chlorophenyl)ethoxy]carbonyl]amino]-3-methyl-5-isoxazolyl]phenyl]methyl]thio]-propanoic acid.
  • the LPA receptor antagonists contemplated for use herein are antagonists of LPAI and optionally at least one of the LPA receptors selected from LPA 2 , LPA 3 , LPA 4; LPA 5 and LPA 6 .
  • the LPA receptor antagonists are antagonists LPAi and/or LP A3.
  • the LPA compounds are antagonists of LPAi and/or LPA 2 .
  • LPA receptor antagonists contemplated for use in any of the embodiments disclosed herein are selective LPAI receptor antagonists.
  • Selectivity for one LPA receptor versus other LPA receptors means that the compound has an IC5 0 (Ca Flux assay) for the indicated LPA receptor that is at least 10-fold less than the IC5 0 for other LPA receptors.
  • selectivity for one LPA receptor versus other LPA receptor means that the compound has an IC5 0 for the indicated LPA receptor that is at least 10-fold, at least 20-fold, at least 40-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 500-fold, or at least 1000-fold, less than the IC 50 for other LPA receptors.
  • a selective LPAi receptor antagonist has an IC5 0 that is at least 10-fold, at least 20-fold, at least 40-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 500-fold, or at least 1000-fold, less than the IC5 0 for other LPA receptors (e.g. LPA 2 , LPA 3 ).
  • pharmaceutically acceptable salts are obtained by reacting an LPA receptor antagonist compound with acids.
  • Pharmaceutically acceptable salts are also obtained by reacting an LPA receptor antagonist compound with a base.
  • LPA receptor antagonists described herein are used as pharmaceutically acceptable salts.
  • the type of pharmaceutical acceptable salts include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable: inorganic acid to form a salt such as, for example, a hydrochloric acid salt, a hydrobromic acid salt, a sulfuric acid salt, a phosphoric acid salt, a metaphosphoric acid salt, and the like; or with an organic acid to form a salt, such as, for example, an acetic acid salt, a propionic acid salt, a hexanoic acid salt, a cyclopentanepropionic acid salt, a glycolic acid salt, a pyruvic acid salt, a lactic acid salt, a malonic acid salt, a succinic acid salt, a malic acid salt, a maleic acid salt, a fumaric acid salt, a trifiuoroacetic acid salt, a tartaric acid salt, a citric acid salt, a benzoic acid salt, a 3-
  • LPA receptor antagonist compounds described herein are reacted with an organic base to form a salt, such as, but not limited to, an ethanolamine salt, a diethanolamine salt, a triethanolamine salt, a tromethamine salt, a N-methylglucamine salt, a dicyclohexylamine salt, a tris(hydroxymethyl)methylamine salt.
  • a salt such as, but not limited to, an ethanolamine salt, a diethanolamine salt, a triethanolamine salt, a tromethamine salt, a N-methylglucamine salt, a dicyclohexylamine salt, a tris(hydroxymethyl)methylamine salt.
  • LPA receptor antagonist compounds described herein form salts with amino acids such as, but not limited to, an arginine salt, a lysine salt, and the like.
  • Acceptable inorganic bases used to form salts with compounds that include an acidic proton include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
  • LPA receptor antagonist compounds are prepared and utilized as sodium salts.
  • the LPA receptor antagonist compounds described herein possess one or more stereocenters and each center exists independently in either the R or S configuration.
  • the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof.
  • LPA antagonists presented herein are used as a single enantiomer. In some embodiments, LPA antagonists presented herein are used as a single enantiomer that is optically pure (i.e. substantially free of the other isomer). In some embodiments, LPA antagonists presented herein are used as a single enantiomer of any optical purity. In some embodiments, LPA antagonists presented herein are used as a racemic mixture.
  • alkyl group refers to an aliphatic hydrocarbon group.
  • the alkyl group may be a saturated alkyl group or an unsaturated alkyl group.
  • the alkyl moiety, whether saturated or unsaturated, may be branched or straight chain.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, hexyl, allyl, but-2-enyl, but-3-enyl, and the like.
  • alkyl is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.
  • alkylene refers to a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl.
  • Typical alkylene groups include, but are not limited to, -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, - CH 2 CH 2 -, -CH 2 CH(CH 3 )-, -CH 2 C(CH 3 ) 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, and the like.
  • alkoxy refers to a (alkyl)O- group, where alkyl is as defined herein.
  • Aryl refers to phenyl or naphthalenyl.
  • an aryl is a phenyl.
  • an aryl group can be a monoradical or a diradical (i.e., an arylene group).
  • Examplary arylenes include, but are not limited to, phenyl- 1,2-ene, phenyl- 1, 3 -ene, and phenyl- 1,4-ene.
  • cycloalkyl refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. Cycloalkyls may be saturated, or partially unsaturated. In some embodiments, cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
  • a cycloalkyl group can be a monoradical or a diradical (i.e., an cycloalkylene group, such as, but not limited to, cyclopropan-l,l-diyl, cyclobutan-l,l-diyl, cyclopentan- 1 , 1 -diyl, cyclohexan- 1 , 1 -diyl, cyclohexan- 1 ,4-diyl, cycloheptan- 1 , 1 -diyl, and the like).
  • an cycloalkylene group such as, but not limited to, cyclopropan-l,l-diyl, cyclobutan-l,l-diyl, cyclopentan- 1 , 1 -diyl, cyclohexan- 1 , 1 -diyl, cyclohexan- 1 ,4-diyl, cyclohept
  • halo or, alternatively, "halogen” or “halide” means fluoro, chloro, bromo or iodo.
  • haloalkyl refers to an alkyl group in which one or more hydrogen atoms are replaced by one or more halide atoms.
  • haloalkyl ene refers to an alkylene group in which one or more hydrogen atoms are replaced by one or more halide atoms.
  • fluoroalkyl refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom.
  • fluoroalkylene refers to an alkylene in which one or more hydrogen atoms are replaced by a fluorine atom.
  • heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g. , oxygen, nitrogen (e.g. NH or Nalkyl), sulfur, or combinations thereof.
  • heteroalkylene refers to an alkylene group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, or combinations thereof.
  • Examplary heteroalkylenes include, but are not limited to, -OCH 2 -, - OCH(CH 3 )-, -OC(CH 3 ) 2 -, -OCH 2 CH 2 -, -CH 2 0-, -CH(CH 3 )0-, -C(CH 3 ) 2 0-, -CH 2 CH 2 0-, -CH 2 OCH 2 - , -CH 2 OCH 2 CH 2 -, -CH 2 CH 2 OCH 2 -, -SCH 2 -, -SCH(CH 3 )-, -SC(CH 3 ) 2 -, -SCH 2 CH 2 -, -CH 2 S-, - CH(CH 3 )S-, -C(CH 3
  • heteroaryl refers to an aromatic ring that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur.
  • Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl.
  • a heteroaryl contains 0-3 N atoms.
  • a heteroaryl contains 1-3 N atoms. In another aspect, a heteroaryl contains 0-3 N atoms, 0-1 O atoms, and 0-1 S atoms. In another aspect, a heteroaryl is a monocyclic or bicyclic heteroaryl. In one aspect, heteroaryl is a Ci-Cgheteroaryl. In one aspect, monocyclic heteroaryl is a Ci-Csheteroaryl. In one aspect, monocyclic heteroaryl is a 5- membered or 6-membered heteroaryl. In one aspect, bicyclic heteroaryl is a C6-C 9 heteroaryl.
  • a heteroaryl group can be a monoradical or a diradical (i.e., a
  • heterocycloalkyl refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur.
  • the heterocycloalkyl is selected from oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and indolinyl.
  • heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides.
  • a heterocycloalkyl is a C 2 -Cioheterocycloalkyl.
  • a heterocycloalkyl is a C4-Cioheterocycloalkyl.
  • a heterocycloalkyl contains 0-2 N atoms.
  • a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms or 0-1 S atoms.
  • membered ring is meant to denote the number of skeletal atoms that constitute the ring.
  • cyclohexyl, pyridinyl, pyranyl and thiopyranyl are 6-membered rings and cyclopentyl, pyrrolyl, furanyl, and thienyl are 5-membered rings.
  • moiety refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
  • an optional substituent is selected from halogen, -CN, -NH 2 , -OH, -NH(CH 3 ), -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CF 3 , - OCH 3 , and -OCF 3 .
  • substituted groups are substituted with one or two of the preceding groups. In some embodiments, substituted groups are substituted with one of the preceding groups. [00197] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof can be chosen by one skilled in the field to provide stable moieties and compounds.
  • the compounds presented herein possess one or more stereocenters and each center independently exists in either the R or S configuration.
  • the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof.
  • Stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns.
  • the methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds having the structure of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI) or Formula (VII), as well as active metabolites of these compounds having the same type of activity.
  • compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.
  • the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In other embodiments, the compounds described herein exist in unsolvated form.
  • module means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.
  • antagonist refers to a molecule such as a compound, which diminishes, inhibits, or prevents the action of another molecule or the activity of a receptor site.
  • Antagonists include, but are not limited to, competitive antagonists, non-competitive antagonists, uncompetitive antagonists, partial agonists and inverse agonists.
  • LPA-dependent refers to conditions or disorders that would not occur, or would not occur to the same extent, in the absence of LPA.
  • LPA-mediated refers to refers to conditions or disorders that might occur in the absence of LPA but can occur in the presence of LPA.
  • an “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound (e.g. an LPA receptor antagonist described herein) being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of an LPA receptor antagonist in an inhalable formulation described herein that is required to provide a clinically significant decrease in disease symptoms.
  • An appropriate "effective" amount in any individual case may be determined using techniques, such as a dose escalation study.
  • the term "subject” or “individual” or “patient” encompasses mammals and non-mammals.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • the mammal is a human.
  • treat include alleviating, abating or ameliorating at least one symptom of a disease disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
  • compositions are administered to an individual suspected of having a particular disorder, at risk of developing a disorder or to an individual reporting one or more symptoms of a disorder or at risk of reocurrence of a disease.
  • Inhalable formulations described herein deliver LPA receptor antagonists to the respiratory tree of a mammal.
  • localized pulmonary administration of an LPA receptor antagonist reduces or eliminates side-effects associated with systemic administration of LPA receptor antagonists.
  • the formulations described herein are administered by a nasal or oral respiratory route and are suitable for delivery of LPA receptor antagonists to the lungs of a mammal.
  • Inhalable formulations described herein include but are not limited to solutions, suspensions, colloidal dispersions, emulsions, sprays, dry powders, aerosols or drops.
  • inhalable formulations that include an LPA receptor antagonist wherein the inhalable formulation is in the form of a solution.
  • pulmonary delivery of an LPA receptor antagonist is achieved by administration of an inhalable solution formulation by the nasal respiratory route of a mammal.
  • the solution is administered by an oral respiratory route to the lungs of a mammal.
  • the solution comprises an LPA receptor antagonist or a salt thereof dissolved in sterile water and/or 0.9% sodium chloride solution. Small quantities of an alcohol or glycerin are used to solubilize the LPA receptor antagonist compound.
  • the solutions comprise a pH modifying agent to solubilize the LPA receptor antagonist.
  • a pH-modifying agent maintains a solution pH of 5.5-7.5 and solubilizes the LPA receptor antagonist (e.g., an acid salt of an LPA receptor antagonist).
  • the solution further comprises a preservative and/or a stabilizer.
  • sterile solutions are obtained in the absence of a preservative and/or a stabilizer using filtration systems (e.g., 0.2 ⁇ filtration systems) and/or heat treatment.
  • the solution comprises a surfactant to enhance solubility of an LPA receptor antagonist.
  • the surfactant concentration is kept as low as possible to minimize foaming that might interfere with proper administration.
  • the inhalable solution formulation is isotonic with physiological fluids (e.g., osmolality of about 290 mOsm). In some instances, the inhalable solution formulation is hypotonic with physiological fluids.
  • the osmolarity of an inhalable formulation is from about 250 to about 450 mOsm/L. In some instances the osmolarityof an inhalable formulation described herein is about 250-300 mOsm/L, about 260-310 mOsm/L, about 270-320 mOsm/L, about 280-330 mOsm/L, about 290-340 mOsm/L, about 300-350 mOsm/L, about 310-360 mOsm/L, or about 320- 370 mOsm/L.
  • an inhalable formulation comprising an LPA- receptor antagonist wherein the inhalable formulation is in the form of an emulsion, a colloidal dispersion or a suspension.
  • the inhalable formulation that is in the form of an emulsion, a colloidal dispersion or a suspension is suitable for pulmonary delivery of LPA receptor antagonists in a mammal.
  • the inhalable formulation that is in the form of an emulsion, a colloidal dispersion or a suspension is administered by the nasal or oral respiratory route in a mammal.
  • suspensions, emulsions or colloidal dispersions comprise a propellant system (e.g., liquified gas) with or without a cosolvent.
  • the fomulations further comprise pH-modifying agents, preservatives and/or stabilizers.
  • sterile formulations are obtained in the absence of a preservative and/or a stabilizer using filtration systems (e.g., 0.2 ⁇ filtration systems) and/or heat treatment.
  • the suspensions, emulsions or colloidal dispersions comprise a surfactant to enhance solubility of an LPA receptor antagonist.
  • the surfactant e.g., liquified gas
  • the liquid phase e.g., a cosolvent
  • the liquid phase has a density similar to the density of the suspensoid.
  • the liquid phase is a cosolvent that partially dissolves or does not dissolve the LPA receptor antagonist, thus minimizing particle size growth resulting from the dissolved compound crystallizing out onto crystals present in the suspenoid.
  • an inhalable formulation described herein is isotonic with physiological fluids (e.g., osmolality of about 290 mOsm). In some instance an inhalable formulation described herein is hypotonic with physiological fluids.
  • the suspensions, emulsions or colloidal dispersions comprise tonicity agents (e.g., sodium chloride, potassium chloride or the like) that render the formulation hypotonic.
  • hypotonic formulations allow for absorption of the LPA receptor antagonist from the pulmonary space into the alveoli.
  • the suspensions, emulsions or colloidal dispersions are aqueous suspensions, emulsions or colloidal dispersions.
  • an inhalable formulation comprising an LPA receptor antagonist wherein the inhalable formulation is in the form of a dry powder.
  • the dry powder inhalable formulation is suitable for administration of an LPA receptor antagonist to the lungs of a mammal.
  • the dry powder inhalable formulation is administered by the nasal or oral respiratory route in a mammal.
  • the dry powder is fluidized when a mammal inhales.
  • dry powders are free of propellants.
  • dry powders are one-phase solid-particle blends. When actuated, in some instances, dry powders are two-phase gas-solid systems wherein the dry powder is dispersed in air.
  • Dry powders comprise micronized and/or nano-sized LPA receptor antagonist particles blended with larger carrier particles that prevent aggregation.
  • the excipients and/or carriers in dry powders are endogenous to the lung and are easily metabolized or cleared.
  • dry powders contain lactose as a carrier.
  • dry powders comprise starch, mannitol or glucose as a carrier.
  • LPA receptor antagonist dry powders are formulated as liposomes comprising phospholipids (e.g., phosphatidylcholine), cholesterol, or the like.
  • a carrier particle has low hygroscopicity (e.g., lactose) to prevent aggregation or caking due to absorption of moisture.
  • a dry powder inhalable formulation described herein comprises nano- particles of an LPA receptor antagonist. In some instances dry powder inhalable formulations described herein comprise crystalline particles. In some embodiments, dry powder inhalable formulations described herein comprise amorphous particles.
  • the pulmonary absorption characteristics of dry powders, suspensions, emulsions and colloidal dispersions are determined by the particle size of the active ingredient (e.g., an LPA receptor antagonist described herein) in the formulation. Particles greater than 60 ⁇ in diameter are deposited in the trachea; particles between 20 - 60 ⁇ in diameter are deposited between the trachea and the bronchioles. Particles between 5-20 ⁇ in diameter are deposited in bronchioles. Particles less than 1 ⁇ in diameter remian airborne and are exhaled. In some instances, the particle size of an LPA receptor antagonist in an inhalable formulation described herein is 5 -20 ⁇ in diameter.
  • aerodynamic diameter of a particle is an appropriate measure of pulmonay absorption characteristics of particles in inhalable formulations described herein because it relates to particle dynamic behaviour. Particles larger than 5 ⁇ aerodynamic diameter deposit in the oral cavity or the pharynx and are cleared. Particles smaller than 1 ⁇ aerodynamic diameter are not deposited and are exhaled. In some instances, the aerodynamic diameter of an LPA receptor antagonist in an inhalable formulation described herein is 1 -5 ⁇ .
  • any inhalable formulation described herein is a multimodal particulate formulation.
  • a multimodal particulate formulation comprises a first population of particles (e.g., LPA receptor antagonist particles) have a first effective mean particle diameter and a second population of particles having a second mean particle diameter wherein the first effective mean particle diameter is at least 1.5 to 3 times the second effective mean particle diameter.
  • Particle size reduction techniques include, by way of example, milling (e.g., air-attrition milling (jet milling), ball milling), spray drying and/or supercritical fluid crystallization.
  • any inhalable formulation described herein is prepared using a suitable particle size detection technique.
  • LPA receptor antagonist particles and/or excipients and/or carriers are sized using cascade impactors.
  • Cascade impactors contain orifices of deceasing size stacked on top of each other. Aerosolized particles are drawn through the impactor and deposit in different stages based on their inertia. Electrical low pressure impactors are a modification of a cascade impactor. The particles are charged before traversing the cascade of stages. The impact of the particles on stages produces an electrical current that is converted into particle-size data.
  • light scattering and/or laser diffraction techniques are used to calculate particle sizes. Different size particles diffract light at different angles and a computer algorithm interprets the diffraction data and calculates a particle size distribution.
  • imaging techniques are used to determine particle size. Digital images of particles are converted to binary data and a particle size data is derived using 2 or 3-dimensional representations of the particles.
  • the inhalable formulations described herein are administered via an atomizer.
  • An atomizer allows a stream of air to move at a high velocity over the tip of a tube dipped in a solution. The pressure at the tip of the tube is lowered and the solution is drawn into the air flow. The solution disperses into a fine spray or droplets that are carried into the inhaled stream of air.
  • the inhalable solution formulations described herein are administered with a nebulizer that is placed in the mouth. The spray, mist or fine droplets produced by atomizers or nebulizers allow the LPA receptor antagonist to reach the bronchioles in the lungs.
  • the inhalable formulations described herein comprise a propellant and are pressure packaged for administration of LP A receptor antagonist(s) using pressurized aerosols.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the inhalable formulations described herein are administered with a metered dose spray bottle that delivers a specific volume of a solution, suspension, emulsion or colloidal dispersion for inhalation.
  • the dry powder inhalable formulations described herein are administered with an insufflator.
  • An insufflator consists of a rubber bulb connected to a container and a delivery pipe.
  • the bulb As the bulb is squeezed, air is blown into the container and causes the powder to move. The particles are carried out via the delivery tube and are inhaled.
  • the dry powder inhalable formulations described herein are administered with a puffer. The dry powder is placed in the puffer and the puffer is squeezed. A portion of the powder is ejected from the spout into the air and is inhaled.
  • Capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator may be formulated containing a dry powder formulation described herein.
  • pH adjusting agents or buffering agents include, but are not limited to acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride.
  • acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids
  • bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane
  • buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride.
  • acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.
  • Tonicity agents are used to adjust the composition of the formulation to the desired isotonic range.
  • Tonicity agents include one or more salts in an amount required to bring osmolality of the composition into an acceptable range.
  • Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.
  • Other exemplary tonicity agents include mannitol, dextrose,
  • Suitable preservatives include benzoic acid, boric acid, p-hydroxybenzoates, alcohols, mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.
  • the formulations described herein optionally include one or more stabilizers (e.g., antioxidants) to enhance chemical stability where required.
  • antioxidants include, by way of example only, ascorbic acid, methionine, sodium thiosulfate and sodium metabisulfite.
  • antioxidants are selected from metal chelating agents, thiol containing compounds and other general stabilizing agents.
  • propellants include one or mixture of chlorofluorocarbons, such as dichlorodifiuoromethane, trichlorofiuoromethane, dichlorotetrafluoroethane or the like, as well as hydrofluorocarbons, such as 1 , 1 , 1 ,2-tetrafluoroethane (HFC- 134a) and 1,1,1,2,3,3,3 -heptafluoropropane (HFC-227) or the like, carbon dioxide or other suitable gas.
  • chlorofluorocarbons such as dichlorodifiuoromethane, trichlorofiuoromethane, dichlorotetrafluoroethane or the like
  • hydrofluorocarbons such as 1 , 1 , 1 ,2-tetrafluoroethane (HFC- 134a) and 1,1,1,2,3,3,3 -heptafluoropropane (HFC-227) or the like, carbon dioxide or other suitable gas
  • the propellants are used with a cosolvent.
  • cosolvents include alcohols such as ethyl alcohol, isopropyl alcohol, propylene glycol, hydrocarbons such as propane, butane, isobutane, pentane, isopentane, neopentane, and other propellants such as those commonly referred to as Propellants 11, 12, 114, 113, 142b, 152a 124, and dimethyl ether.
  • surfactants are wetting agents that lower the surface tension of a liquid.
  • surfactants for inhalable formulations include and are not limited to oils derived from natural sources, such as, corn oil, olive oil, cotton seed oil and sunflower seed oil; sorbitan esters, such as Sorbitan trioleate available under the trade name Span 85, Sorbitan mono-oleate available under the trade name Span 80, Sorbitan monolaurate available under the trade name Span 20, Polyoxyethylene (20) sorbitan monolaurate available under the trade name Tween 20, Polyoxyethylene (20) sorbitan mono-oleate available under the trade name Tween 80; lecithins derived from natural sources such as those available under the trade name Epikuron particularly Epikuron 200.
  • Polyethylene glycol 400 Polyethylene glycol 400, and Cetyl pyridinium chloride.
  • the aqueous suspensions, emulsions and colloidal dispersions described herein remain in a homogenous state, as defined in The USP Pharmacists' Pharmacopeia (2005 edition, chapter 905), for at least 4 hours.
  • an aqueous suspension is re-suspended into a homogenous suspension by physical agitation lasting less than 1 minute (e.g., by shaking a metered spray dispenser).
  • no agitation is necessary to maintain a homogeneous aqueous dispersion.
  • the solution, emulsion, suspension and/or colloidal dispersion formulations also include inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and/or emulsifiers.
  • Exemplary emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, sodium lauryl sulfate, sodium doccusate, cholesterol, cholesterol esters, taurocholic acid, phosphotidylcholine, oils, such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan, or mixtures of these substances, and the like.
  • the inhalable formulations described herein are stable (e.g., with respect to pH, active ingredient) over a period of any of at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, at least about 8 weeks, at least about 4 months, at least about 5 months, at least about 6 months, or greater than 6 months.
  • the inhalable formulations described herein are designed for minimal pulmonary toxicity, irritation and/or allergic challenge to pulmonary tissues and include, for example, low amounts of excipients such as surfactants, preservatives and/or cosolvents.
  • an inhalable formulation of an LPA receptor antagonist compound wherein the inhalable formulation is administered for prophylactic and/or therapeutic treatments.
  • amounts effective for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the mammal's health status and response to the drugs, and the judgment of the treating physician.
  • the dose of an LPA receptor antagonist is about 0.001% by weight to about 10% by weight of the inhalable formulation. In some embodiments, the dose of an LPA receptor antagonist is about 0.001%) by weight to about 5%> by weight of the inhalable formulation.
  • an inhalable formulation disclosed herein is administered chronically (i.e., for an extended period of time, including throughout the duration of the mammal's life). In some embodiments, where an LPA-dependent or LPA-mediated disease or condition does improve, an inhalable formulation disclosed herein is given continuously; alternatively, the dose of active agent being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday"). In some embodiments, a drug holiday lasts between 2 days and 1 year, including all integers in between. In some embodiments, the dose reduction during a drug holiday is from about 10%) to about 100%), including all integers in between.
  • an inhalable formulation disclosed herein is administered as a maintenance dose. In some embodiments, where an LPA-dependent or LPA-mediated disease or condition does improve, an inhalable formulation disclosed herein is administered with reduced frequency or at a reduced dose.
  • an inhalable formulation disclosed herein is administered as a prophylactic dose prior to onset of disease symptoms.
  • a prophylactic dose is a reduced dose compared to a therapeutic dose.
  • the inhalable formulations described herein are generally administered in volumes of 25-250 ⁇ ⁇ per metered dose. In some instances, the inhalable formulations described herein are administered in volumes of less than 250 ⁇ , less than 150 ⁇ , less than 100 ⁇ , or less than 50 ⁇ L ⁇ .
  • any of the aforementioned embodiments are further embodiments comprising single administrations of the effective amount of the LPA receptor antagonist, including further
  • any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the LPA receptor antagonist, including further
  • the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed.
  • the length of the drug holiday varies from 2 days to 1 year.
  • any of the aforementioned aspects involving the prevention or treatment of LPA- mediated diseases or conditions of the eye are further embodiments comprising identifying patients by screening for LPA receptor gene SNPs. Patients can be further selected based on increased LPA receptor expression in the tissue of interest. LPA receptor expression are determined by methods including, but not limited to, northern blotting, western blotting, quantitative PCR (qPCR), flow cytometry, autoradiography (using a small molecule radioligand or PET ligand). In some of the tissue of interest. LPA receptor expression are determined by methods including, but not limited to, northern blotting, western blotting, quantitative PCR (qPCR), flow cytometry, autoradiography (using a small molecule radioligand or PET ligand). In some of the tissue of interest. LPA receptor expression are determined by methods including, but not limited to, northern blotting, western blotting, quantitative PCR (qPCR), flow cytometry, autoradiography (using a small molecule radioligand or PET ligand). In some
  • patients are selected based on the concentration of serum or tissue LPA measured by mass spectrometry. In some embodiments, patients are selected based on a combination of the above markers (increased LPA concentrations and increased LPA receptor expression).
  • At least one LPA receptor antagonist in combination with another therapeutic agent.
  • another therapeutic agent such as one of the side effects experienced by a patient upon receiving one of the compounds herein is inflammation, then it may be appropriate to administer an anti-inflammatory agent in combination with the initial therapeutic agent.
  • a patient is presented with a situation in which antagonism of LPA receptors provides potential harm, for example, if the patient is wounded, antagonism of LPA receptors may lead to a delay in wound healing.
  • the patient benefits by administration of a local wound-healing agent (at the site of the wound) in combination with the co-existing administration of a LPA receptor antagonist.
  • the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant ⁇ i.e., by itself the adjuvant may have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
  • the benefit experienced by a patient is increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
  • a LPA receptor antagonist is co-administered with a second therapeutic agent, wherein the LPA receptor antagonist and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.
  • the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit.
  • different therapeutically-effective dosages of the compounds disclosed herein will be utilized in formulating pharmaceutical composition and/or in treatment regimens when the compounds disclosed herein are administered in combination with one or more additional agent, such as an additional therapeutically effective drug, an adjuvant or the like.
  • a combination treatment regimen encompasses treatment regimens in which administration of a LPA receptor antagonist is initiated prior to, during, or after treatment with a second agent described herein, and continues until any time during treatment with the second agent or after termination of treatment with the second agent. It also includes treatments in which a LPA receptor antagonist and the second agent being used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period.
  • Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.
  • compositions and methods for combination therapy are provided herein.
  • the pharmaceutical compositions disclosed herein are used to treat LPA-dependent or LPA-mediated conditions.
  • the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought is modified in accordance with a variety of factors. These factors include the disease, disorder or condition from which the subject suffers, as well as the age, weight, sex, diet, and medical condition of the subject. Thus, in some instances, the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.
  • dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated and so forth.
  • the compound provided herein when co-administered with one or more other therapeutic agents, is administered either simultaneously with the one or more other therapeutic agents, or sequentially.
  • the multiple therapeutic agents are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms. In one embodiment, one of the therapeutic agents is given in multiple doses, and in another, two (or more if present) are given as multiple doses. In some embodiments of non-simultaneous administration, the timing between the multiple doses vary from more than zero weeks to less than four weeks. In addition, the combination methods, compositions and formulations are not to be limited to the use of only two agents; the use of multiple therapeutic combinations is also envisioned.
  • the LPA receptor antagonist and combination therapies are administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies.
  • the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition.
  • the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms.
  • a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease.
  • the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject.
  • a compound described herein or a formulation containing the compound is administered for at least 2 weeks, about 1 month to about 5 years.
  • therapies which combine a LPA receptor antagonist with inhibitors of LPA synthesis or LPA receptor antagonists, either acting at the same or other points in the LPA synthesis or signalling pathway, are encompassed herein for treating LPA-dependent or LPA- mediated diseases or conditions.
  • compositions and methods disclosed herein include an additional therapeutic agent.
  • the additional therapeutic agent is a therapeutic agent other than a LPA antagonist.
  • compositions disclosed herein that include a LPA receptor antagonist are co-administered with one or more additional therapeutically active agents selected from: corticosteroids, immunosuppresants, analgesics, anti-cancer agent, antiinflammatories, chemokine receptor antagonists, bronchodilators, leukotriene receptor antagonists, leukotriene formation inhibitors, monoacylglycerol kinase inhibitors, phospholipase Ai inhibitors, phospholipase A 2 inhibitors, and lysophospho lipase D (lysoPLD) inhibitors, autotaxin inhibitors, decongestants, antihistamines, mucolytics, anticholinergics, antitussives, expectorants, and ⁇ -2 agonists.
  • additional therapeutically active agents selected from: corticosteroids, immunosuppresants, analgesics, anti-cancer agent, antiinflammatories, chemokine receptor antagonists, bronchodil
  • compositions disclosed herein that include a LPA receptor antagonist are co-administered with (either separately or in the same formulation) an antibiotic.
  • Antibiotics include, but are not limited to, polymyxin B sulfate / bacitracin zinc, polymyxin B / neomycin / gramicidin, polymyxin B/trimethoprim, polymyxin B/bacitracin, fluoroquinolones (e.g., ciprofloxacin, moxifloxacin, ofloxacin, gatifloxacin, levofloxacin), aminoglycosides (e.g. tobramycin, azithromycin, gentamicin, erythromycin, bacitracin.
  • the pharmaceutical compositions disclosed herein that include a LPA receptor antagonist are co-administered with (either separately or in the same formulation) a leukotriene modulator.
  • Leukotriene modulators include, but are not limited to, 5-lipoxygenase inhibitors (5-LO) inhibitiors, 5-lipoxygenase activating protein (FLAP) inhibitor compounds, LTA 4 hydrolase inhibitors, leukotriene receptor antagonist (e.g. CysLTi receptor antagonists, BLTiR antagonists).
  • the LPA receptor antagonist is co-administered with (either separately or in the same formulation) an antiviral agent.
  • Antiviral agents include, but are not limited to, acyclovir, vidarabine, trifluridine.
  • the LPA receptor antagonist is co-administered with (either separately or in the same formulation) cyclosporine.
  • the LPA receptor antagonist is co-administered with (either separately or in the same formulation) a leukotriene modulator.
  • Leukotriene modulators include, but are not limited to 5-lipoxygenase (5-LO) inhibitors inhibitors, 5-lipoxygenase activating protein (FLAP) inhibitor compounds and leukotriene receptor antagonist (e.g. CysLTi receptor antagonists).
  • a LPA receptor antagonist is used to treat or reduce fibrosis in a mammal.
  • a LPA antagonist is administered in combination with one or more immunosuppresants.
  • Immunosuppressive therapy is clinically used to treat or prevent the rejection of transplanted organs and tissues; treatment of autoimmune diseases or diseases that are most likely of autoimmune origin; treatment of some other non-autoimmune inflammatory diseases, and in the treatment of fibrotic conditions.
  • a LPA receptor antagonist is adminsitered with corticosteroids.
  • a LPA antagonist is adminsitered with an a therapeutic agent selected from among: Calcineurin inhibitors (such as, but not limited to, cyclosporin, tacrolimus); mTOR inhibitors (such as, but not limited to, sirolimus, everolimus); anti-proliferatives (such as, but not limited to, azathioprine, mycophenolic acid); corticosteroids (such as, but not limited to, prednisone, cortisone acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone, hydrocortisone); antibodies (such as, but not limited to, monoclonal anti-IL-2Ra receptor antibodies (
  • Other therapeutic agents include, but are not limited to: cyclophosphamide, penicillamine, cyclosporine, nitrosoureas, cisplatin, carboplatin, oxaliplatin, methotrexate, azathioprine, mercaptopurine, pyrimidine analogues, protein synthesis inhibitors, dactinomycin, anthracyclines, mitomycin C, bleomycin, mithramycin, Atgam ⁇ , Thymoglobuline ® , OKT3 ® , basiliximab, daclizumab, cyclosporin, tacrolimus, sirolimus, Interferons (IFN- ⁇ , IFN- ⁇ ), opioids, TNF binding proteins (infliximab, etanercept, adalimumab, golimumab), leflunomide, gold thioglucose, gold thiomalate, aurofin,
  • a LPA antagonist is administered in combination with Cyclosporin A (CsA) or tacrolimus (FK506).
  • a LPA antagonist is administered to a mammal in combination with an anti-inflammatory agent including, but not limited to, non-steroidal anti- inflammatory drugs (NSAIDs) and corticosteroids (glucocorticoids).
  • NSAIDs non-steroidal anti- inflammatory drugs
  • corticosteroids corticosteroids
  • NSAIDs include, but are not limited to: aspirin, salicylic acid, gentisic acid, choline magnesium salicylate, choline salicylate, choline magnesium salicylate, choline salicylate, magnesium salicylate, sodium salicylate, diflunisal, carprofen, fenoprofen, fenoprofen calcium, flurobiprofen, ibuprofen, ketoprofen, nabutone, ketolorac, ketorolac tromethamine, naproxen, oxaprozin, diclofenac, etodolac, indomethacin, sulindac, tolmetin, meclofenamate, meclofenamate sodium, mefenamic acid, piroxicam, meloxicam, COX-2 specific inhibitors (such as, but not limited to, celecoxib, rofecoxib, valdecoxib, parecoxib, e
  • Corticosteroids include, but are not limited to: betamethasone, prednisone, alclometasone, aldosterone, amcinonide, beclometasone, betamethasone, budesonide, ciclesonide, clobetasol, clobetasone, clocortolone, cloprednol, cortisone, cortivazol, deflazacort, deoxycorticosterone, desonide, desoximetasone, desoxycortone, dexamethasone, diflorasone, diflucortolone, difluprednate, fluclorolone, fludrocortisone, fludroxycortide, flumetasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin, fluocortolone, fluorometholone, fluperolone, fluprednidene, flu
  • a LPA receptor antagonist is administered in combination with leukotriene receptor antagonists including, but are not limited to, BAY u9773 (see EP 00791576), DUO-LT (Tsuji et al, Org. Biomol. Chem., 1, 3139-3141, 2003), zafirlukast, montelukast, prankulast, and derivatives or analogs thereof.
  • leukotriene receptor antagonists including, but are not limited to, BAY u9773 (see EP 00791576), DUO-LT (Tsuji et al, Org. Biomol. Chem., 1, 3139-3141, 2003), zafirlukast, montelukast, prankulast, and derivatives or analogs thereof.
  • an LPA receptor antagonist is administered in combination with agents to increase blood flow, including nifedipine, amlodipine, diltiazem, felodipine, or nicardipine.
  • an LPA receptor antagonist is administered in combination with methotrexate, cyclophosphamide, azathioprine, or mycophenolate.
  • an LPA receptor antagonist is administered in combination with pirfenidone.
  • the LPA antagonist and the additional therapeutic agent are in the same pharmaceutical composition. In some embodiments, the LPA receptor antagonist and the additional therapeutic agent are in separate pharmaceutical compositions. In some embodiments, the LPA receptor antagonist and the additional therapeutic agent are in separate pharmaceutical compositions wherein the LPA receptor antagonist is administered by inhalation and the additional therapeutic agent is administered by the same route or by a different route. In some embodiments, the LPA receptor antagonist and the additional therapeutic agent are administered at the same time. In some embodiments, the LPA receptor antagonist and the additional therapeutic agent are administered at different times.
  • Example 1 Inhalable solution formulation (preservative free)
  • LPA receptor antagonist, citric acid and sodium chloride are dissolved in water and the solution is filtered through a 0.2 ⁇ filter system and packaged in sterile metered spray bottles.
  • Example 2 Inhalable solution formulation with preservative
  • LPA receptor antagonist, and sodium chloride are dissolved in water, hydrochloric acid and benzalkonium chloride are added. The solution is filtered through a 0.2 ⁇ filter system and packaged in sterile metered spray bottles.
  • LPA receptor antagonist is suspended in water, Span 85 is added followed by addition of dextrose and ascorbic acid. Benzalkonium chloride is added and the pH is adjusted to 7 with phosphate buffer. The suspension is packaged in sterile nebulizers.
  • Example 4 Inhalable emulsion formulation for aerosols
  • LPA receptor antagonist is suspended in HFC-227, ethyl alcohol is added followed by addition of Span 85 and ascorbic acid. The pH is adjusted to 7 with phosphate buffer. The emulsion is packaged in sterile aerosol metered spray bottles.
  • LPA receptor antagonist 50 g is jet milled to obtain a median particle size diameter of 3-4 ⁇ .
  • Lactose (5 kg) is jet milled to a median particle size diameter of 5 ⁇ .
  • the ingredients are mixed in a blender bowl at 40-50 rpm and the final mixture is packaged in sterile insufflators.
  • Example 6 Establishment of a CHO Cell Line Stably Expressing Human LPA ⁇ [00274]
  • a 1.1 kb cDNA encoding the human LPAi receptor was cloned from human lung.
  • Human lung RNA (Clontech Laboratories, Inc. USA) was reverse transcribed using the RETROscript kit (Ambion, Inc.) and the full-length cDNA for human LPAi was obtained by PCR of the reverse transcription reaction.
  • the nucleotide sequence of the cloned human LPAi was determined by sequencing and confirmed to be identical to the published human LPAi sequence (An et al. Biochem. Biophys. Res. Commun. 231 :619 (1997).
  • the cDNA was cloned into the pCDNA5/FRT expression plasmid and transfected in CHO cells using lipofectamine 2000 (Invitrogen Corp., USA). Clones stably expressing human LPAi were selected using hygromycin and identified as cells that show Ca- influx in response to LPA.
  • An expression vector encoding thehuman LPA 2 cDNA was transiently transfected into B103 cells using LipofectamineTM 2000 (Invitrogen) following the manufacturers instruction. On the day before the assay, 30,000-35,000 cells/well were seeded together with 0.2 ⁇ lipofectamine 2000 and 0.2 ⁇ g human LPA2 expression vector in 96-well Poly-D-Lysine coated black-wall clear-bottom plates (BD BioCoat) in DMEM + 10% FBS. Following an overnight culture, cells were washed once with PBS then cultured in serum-free media for 4 hours prior to start of the calcium flux assay.
  • LipofectamineTM 2000 Invitrogen
  • Example 8 Establishment of a CHO Cell Line Stably Expressing Human LPA
  • a vector containing the human LPA 3 receptor cDNA was obtained from the Missouri S&T cDNA Resource Center (www.cdna.org). The full-length cDNA fragment for human LPA 3 was obtained by PCR from the vector. The nucleotide sequence of the cloned human LPA 3 was determined by sequencing and confirmed to be identical to the published human LPA 3 sequence (NCBI accession number NM_012152). The cDNA was cloned into the pCDNA5/FRT expression plasmid and transfected in CHO cells using lipofectamine 2000 (Invitrogen Corp., USA). Clones stably expressing human LPA 3 were selected using hygromycin and identified as cells that show Ca- influx in response to LPA.
  • Human LPAi or LPA 3 expressing CHO cells are seeded at 20,000-45,000 cells per well in a 96-well poly-D-lysine coated plate one or two days before the assay. Prior to the assay, the cells are washed once with PBS and then cultured in serum- free media for at least 6 hrs and up to 24hrs . On the day of the assay, a calcium indicator dye (Calcium 5, Molecular Devices) in assay buffer (HBSS with Ca 2+ and Mg 2+ and containing 20 mM Hepes and 0.3%) fatty-acid free human serum albumin) is added to each well and incubation continued for 1 hour at room temperature.
  • assay buffer HBSS with Ca 2+ and Mg 2+ and containing 20 mM Hepes and 0.3%) fatty-acid free human serum albumin
  • LPA2 calcium flux is measured using at least one of two different assays.
  • BT- 20 human breast cancer cells are seeded at 25,000-35,000 cells per well in 150 ⁇ complete media on Poly-D-Lysine coated black-wall clear-bottom plates. Following an overnight culture, cells are washed once with PBS then serum starved for 4-6 hours prior to the assay.
  • a calcium indicator dye (Calcium 5, Molecular Devices) in assay buffer (HBSS with Ca 2+ and Mg 2+ and containing 20 mM Hepes and 0.3% fatty-acid free human serum albumin) is added to each well and incubation continued for 15 minutes at 37°C. 25 ⁇ of test compounds in 2.5% DMSO are added to the cells and incubation continued at 37°C for 15-30 minutes.
  • Cells are the stimulated by the addition of 100 nM LPA and intracellular Ca 2+ measured using the Flexstation 3 (Molecular
  • IC5 0 S are determined using Symyx Assay Explorer analysis of drug titration curves
  • B 103 cells transiently expressing huma LPA2 are serum starved for 4 hours.
  • a calcium indicator dye (Calcium 4, Molecular Devices) in assay buffer (HBSS with Ca 2+ and Mg 2+ and containing 20 mM Hepes and 03% fatty-acid free human serum albumin) is then added to each well and incubation continued for 1 hour at 37°C.
  • 10 ⁇ of test compounds in 2.5% DMSO are added to the cells and incubation continued at room temperature for 30 minutes.
  • Cells are the stimulated by the addition of 10 nM LPA and intracellular Ca 2+ measured using the Flexstation 3 (Molecular Devices).
  • IC 50 s are determined using Symyx Assay Explorer analysis of drug titration curves.
  • CHO cells stably expressing the recombinant human LPAi receptor are resuspended in 10 mM Hepes, 7.4 containing 1 mM DTT, lysed and centrifuged at 75,000 xg to pellet the membranes.
  • the membranes are resuspended in 10 mM Hepes, 7.4 containing 1 mM DTT and 10%) glycerol.
  • Membranes ( ⁇ 25 ⁇ g per well) are incubated in 96-well plates with 0.1 nM [ 35 S]- GTPyS, 900 nM LPA, 5 ⁇ GDP, and test compound in Assay Buffer (50 mM Hepes, pH 7.4, 100 mM NaCl, 10 mM MgCl 2 , 50 ⁇ g/ml saponin and 0.2%> fatty-acid free human serum albumin) for 30 minutes at 30°C. The reactions are terminated by rapid filtration through Whatman GF/B glass fibre filter plates.
  • the filter plates are washed 3 times with 1 ml cold Wash Buffer (50 mM Hepes, 7.5, 100 mM NaCl and 10 mM MgC ⁇ ) and dried. Scintillant is then added to the plates and the radioactivity retained on the filters is determined on a Packard TopCount (Perkin Elmer). Specific binding is determined as total radioactive binding minus non-specific binding in the absence of the ligand (900 nM LPA). IC 50 s were determined using Graphpad prism analysis of drug titration curves.
  • Chemotaxis of the A2058 human melanoma cells was measured using the Neuroprobe ChemoTx® System plates (8 ⁇ pore size, 5.7 mm diameter sites). The filter sites were coated with 0.001% fibronectin (Sigma) in 20 mM Hepes, pH 7.4 and allowed to dry. A2058 cells were serum- starved for 24 hours , then harvested with Cell Stripper and resuspended in DMEM containing 0.1% fatty-acid- free bovine serum albumin (BSA) to a concentration of 1 x 10 6 /ml.
  • BSA bovine serum albumin
  • mice Female C57B1/6 mice (Harlan, 25-30g) are housed 4 per cage, given free access to food and water and allowed to acclimate for at least 7 days prior to test initiation. After the habituation phase, mice are lightly anesthetized with isoflurane (5% in 100% 0 2 ) and administered with bleomycin sulfate (0.01-5 U/kg, Henry Schein) via intratracheal instillation (Cuzzocrea S et al. Am J Physiol Lung Cell Mol Physiol. 2007 May;292(5):L1095-104. Epub 2007 Jan 12.). Mice are returned to their cages and monitored daily for the duration of the experiment. Test compound or vehicle is delivered po, ip or sc daily. The route and frequency of dosing is based on previously determined
  • mice are intubated with a 20 gauge angiocatheter attached to a 1 ml syringe. Lungs are lavaged with saline to obtain bronchoalveolar lavage fluid (BALF) and then removed and fixed in 10%) neutral buffered formalin for subsequent histopathological analysis. BALF is centrifuged for 10 min at 800 x g to pellet the cells and the cell supernatant removed and frozen at -80 °C for subsequent protein analysis using the DC protein assay kit (Biorad, Hercules, CA.) and soluble collagen analysis using Sircol (Biocolor Ltd, UK).
  • BALF bronchoalveolar lavage fluid
  • BALF is analyzed for concentrations of inflammatory, pro-fib rotic and tissue injury biomarkers including transforming growth factor ⁇ , hyaluronic acid, tissue inhibitor of metalloproteinase- 1 , matrix matelloproteinase-7, connective tissue growth factor and lactate dehydrogenase activity, using commercially available ELISA.
  • the cell pellet is re-suspended in PBS.
  • Total cell counts are then obtained using a Hemavet hematology system (Drew Scientific, Wayne, PA.) and differential cells counts are determined using Shandon cytospin (Thermo Scientific, Waltham, MA.).
  • Lung tissue is stained using hematoxylin and eosin (H&E) and tri chrome and lung fibrosis. is determined by semiquantitative histopathological scoring (Ashcroft T. et al. J. Clin. Path. 1988;41;4, 467-470) using light microscopy (lOx magnification) and quantitative, computer-assisted densitometry of collagen in lung tissue sections using light microscopy. The data are plotted using Graphpad prism and statistical differences between groups determined.
  • H&E hematoxylin and eosin
  • Compound A reduced total protein, lactate and TIMP-1 in the BALF in the acute setting (3- day).
  • Compound A decreased inflammatory cell influx and fibrosis after a single bleomycin instillation (3.0 units) in the chronic setting (14-days only).
  • Compound B significantly reduced total protein and collagen concentrations in broncheoalveolar lavage fluid (BALF). In a 7-day bleomycin model compound B reduced BALF collagen, protein, TGF i, MMP-7, hyaluronan, and inflammatory cell influx. In the chronic setting (14 day bleomycin model), Compound B decreased total lung collagen when dosed either propylactically (day 0 - day 14) or therapeutically (day 3 - day 14).
  • BALF broncheoalveolar lavage fluid
  • a mouse intravenous LPA-induced histamine release model is utilized to determine the in vivo potency of LPAi and LP A3 receptor antagonists.
  • Female CD-I mice (weighing 25 - 35 grams) are administered compound (i.p., s.c. or p.o.) in a volume of lOml/kg 30 minutes to 24 hours prior to intravenous LPA challenge (300 ⁇ g/mouse in 0.1% FAF BSA).
  • LPA challenge mice are placed into an enclosed Plexiglas chamber and exposed to an isoflurane for a period of 2 minutes. They are removed, decapitated and trunk blood collected into tubes containing EDTA.
  • Plasma samples Blood is then centrifuged at 10,000 X g for 10 minutes at 4 ° C. Histamine concentrations in the plasma are determined by EIA. Drug concentrations in plasma are determined by mass spectrometry. The dose to achieve 50% inhibition of blood histamine release is calculated by nonlinear regression (Graphpad Prism) and plotted as the ED5 0 . The plasma concentration associated with this dose is plotted as the EC 50 .
  • the primary outcome variable is the absolute change in percent predicted forced vital capacity (FVC) from baseline to Week 72.
  • Secondary outcome measures include: composite outcomes of important IPF-related events; progression- free survival; categorical assessment of absolute change in percent predicted FVC from baseline to Week 72; change in Shortness-of-Breath from baseline to Week 72; change in percent predicted hemoglobin (Hb)-corrected carbon monoxide diffusing capacity (DLco) of the lungs from baseline to Week 72; change in oxygen saturation during the 6 minute walk test (6MWT) from baseline to Week 72; change in high-resolution computed tomography (HRCT) assessment from baseline to Week 72; change in distance walked in the 6MWT from baseline to Week 72.
  • RCT computed tomography
  • Patients eligible for this study include those patients that satisfy the following inclusion criteria: diagnosis of IPF; 40 to 80 years of age; FVC > 50% predicted value; DLco > 35% predicted value; either FVC or DLco ⁇ 90% predicted value; no improvement in past year; able to walk 150 meters in 6 minutes and maintain saturation > 83%) while on no more than 6 L/min supplemental oxygen.
  • Patients are excluded from this study if they satisfy any of the following criteria: unable to undergo pulmonary function testing; evidence of significant obstructive lung disease or airway hyper- responsiveness; in the clinical opinion of the investigator, the patient is expected to need and be eligible for a lung transplant within 72 weeks of randomization; active infection; liver disease; cancer or other medical condition likely to result in death within 2 years; diabetes; pregnancy or lactation; substance abuse; personal or family history of long QT syndrome; other IPF treatment; unable to take study medication; withdrawal from other IPF trials.
  • Patients are dosed with either placebo or inhalable formulation of LPA receptor antagonist.
  • the primary outcome variable will be the absolute change in percent predicted FVC from Baseline to Week 72.
  • Patients will receive blinded study treatment from the time of randomization until the last patient randomized has been treated for 72 weeks.
  • a Data Monitoring Committee (DMC) will periodically review safety and efficacy data to ensure patient safety.
  • IPF Progression of Disease
  • Permitted IPF therapies include corticosteroids, azathioprine, cyclophosphamide and N-acetyl- cysteine.

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Abstract

Described herein are inhalable pharmaceutical compositions comprising LPA receptor anatgonists wherein the pharmaceutical compositions facilitate delivery of LPA receptor antagonists to the lungs of a mammal. Also provided are methods of treating or preventing LPA-dependent or LPA-mediated diseases or conditions in a mammal by pulmonary administration of LPA receptor antagonists.

Description

INHALABLE FORMULATIONS OF LYSOPHOSPHATIDIC ACID RECEPTOR
ANTAGONISTS
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S provisional patent application no. 61/355,093 entitled "INHALABLE FORMULATIONS OF LYSOPHOSPHATIDIC ACID RECEPTOR
ANTAGONISTS" filed on June 15, 2010, which is incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] Described herein are inhalable formulations that include at least one lysophosphatidic acid (LPA) receptor antagonist, and methods of using such formulations to treat or prevent diseases, disorders or conditions mediated by one or more of the LPA receptors.
BACKGROUND OF THE INVENTION
[0003] Lysophosphatidic acid (LPA) binding to its cognate G-protein coupled receptors (LPAl5 LPA2, LP A3, LPA4, LPA5) activates intracellular signaling pathways and produces a variety of biological responses. Inhaled formulations of LPA receptor antagonists, administered to the lungs of a mammal, are used to prevent, ameliorate or treat LPA-dependent or LPA-mediated diseases or conditions.
SUMMARY OF THE INVENTION
[0004] Described herein, in some embodiments, are inhalable formulations for treating LPA- dependent or LPA-mediated diseases or conditions. The formulations described herein are suitable for oral or nasal inhalation. The inhalable formulations described herein include one or more LPA receptor antagonists and allow for rapid delivery of a therapeutically effective amount of an LPA receptor antagonist into the circulatory system and/or target organ (e.g., the lungs) of a mammal in need thereof. Pulmonary administration of an inhalable formulation described herein reverses, ameliorates, treats or prevents diseases or conditions in which the physiological activity of LPA is involved in the etiology or pathology of a disease or condition, or is otherwise associated with at least one symptom of a disease or condition.
[0005] Provided herein is an inhalable formulation comprising an LPA receptor antagonist and at least one pharmaceutically acceptable excipient, wherein the formulation is in a form suitable for administration to the lungs of a mammal. In some embodiments, the inhalable formulation comprising an LPA receptor antagonist in an amount effective for the treatment of an LPA-dependent or LPA-mediated disease or condition. In some embodiments, the LPA-dependent or LPA-mediated disease or condition is a disease or condition as described herein. In some embodiments, the inhalable formulation is a solution, suspension, emulsion, colloidal dispersion, or dry powder, wherein the formulation is suitable for administration to the lungs of a mammal.
[0006] Provided herein is an inhalable formulation comprising an LPA receptor antagonist in an amount effective for the treatment of an LPA-dependent or LPA-mediated disease or condition, and at least one pharmaceutically acceptable excipient to provide a solution, suspension, emulsion, colloidal dispersion, or dry powder, wherein the formulation is in a form suitable for administration to the lungs of a mammal.
[0007] Also provided herein is an inhalable formulation comprising an LPA receptor antagonist in an amount effective for antagonizing LPA receptors, and at least one pharmaceutically acceptable excipient to provide a solution, suspension, emulsion, colloidal dispersion, or dry powder for administration to the lungs of a mammal.
[0008] In some embodiments, the LPA-dependent or LPA-mediated disease or condition is lung cancer, asthma, obstructive pulmonary disease (COPD), pulmonary fibrosis, idiopathic pulmonary fibrosis, radiation induced fibrosis, silicosis, asbestos induced pulmonary or pleural fibrosis, acute lung injury, acute respiratory distress syndrome (ARDS), usual interstitial pneumonia (UIP), cystic fibrosis, Chronic lymphocytic leukemia (CLL)-associated fibrosis, Hamman-Rich syndrome, Caplan syndrome, coal worker's pneumoconiosis, cryptogenic fibrosing alveolitis, obliterative bronchiolitis, chronic bronchitis, emphysema, Wegner's granulamatosis, or interstitial lung disease.
[0009] In some embodiments, the LPA-dependent or LPA-mediated disease or condition is lung cancer, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), usual interstitial pneumonia (UIP), cystic fibrosis, Chronic lymphocytic leukemia (CLL)-associated fibrosis, Hamman-Rich syndrome, Caplan syndrome, coal worker's pneumoconiosis, silicosis, interstitial lung disease, asbestos induced pulmonary or pleural fibrosis, cryptogenic fibrosing alveolitis, or obliterative bronchiolitis.
[0010] In some embodiments, the LPA-dependent or LPA-mediated disease or condition is idiopathic pulmonary fibrosis. In some embodiments, the LPA-dependent or LPA-mediated disease or condition is cystic fibrosis.
[0011] In some embodiments, the LPA-dependent or LPA-mediated disease or condition is Chronic lymphocytic leukemia (CLL)-associated fibrosis. In some embodiments, the LPA-dependent or LPA-mediated disease or condition is silicosis.In some embodiments, the LPA-dependent or LPA- mediated disease or condition is asthma or chronic obstructive pulmonary disease (COPD).
[0012] In some embodiments, the inhalable formulation comprises an LPA receptor antagonist that has a structure of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI) or Formula (VII), or a pharmaceutically acceptable salt thereof. In some embodiments, the inhalable formulation comprises an LPA receptor antagonist that has a structure of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the inhalable formulation comprises an LPA receptor antagonist that has a structure of Formula (II), or a pharmaceutically acceptable salt thereof. In some embodiments, the inhalable formulation comprises an LPA receptor antagonist that has a structure of Formula (III), or a pharmaceutically acceptable salt thereof. In some embodiments, the inhalable formulation comprises an LPA receptor antagonist that has a structure of Formula (IV), or a pharmaceutically acceptable salt thereof. In some embodiments, the inhalable formulation comprises an LPA receptor antagonist that has a structure of Formula (V), or a pharmaceutically acceptable salt thereof. In some embodiments, the inhalable formulation comprises an LPA receptor antagonist that has a structure of Formula (VI) or a pharmaceutically acceptable salt thereof. In some embodiments, the inhalable formulation comprises an LPA receptor antagonist that has a structure of Formula (VII), or a pharmaceutically acceptable salt thereof.
[0013] In some embodiments, the inhalable formulation comprises an LPA receptor antagonist wherein the LPA receptor antagonist is an antagonist of one or more LPA receptors selected from LPAi, LPA2, LPA3, LPA4 and LPA5. In some embodiments, the inhalable formulation comprises an LPA receptor antagonist wherein the LPA receptor antagonist is an antagonist of LPA i.
[0014] In some embodiments, the inhalable formulation comprises an LPA receptor antagonist that is a selective LPAi antagonist.
[0015] In some embodiments, the inhalable formulation comprises an LPAi antagonist that is described in US Provisional Application no. 61/122,568; US Provisional Application no. 61/183,785; US Patent Application no. 12/638,702; US Provisional Application no. 61/121,862; US Provisional Application no. 61/231,282; US Provisional Application no. 61/247,681; US Provisional Application no. 61/2472877; International patent application no. PCT/US2010/44284; International patent application no. PCT/US2010/51199; International patent application no. PCT/US2010/51150; US Patent Application no. 12/896,080; International patent application no. PCT/US2010/50786;
International patent application no. PCT/US2010/50787; US Patent Application no. 12/893,902; International patent application no. PCT/US09/68106; International patent application no.
PCT/U S09/68105; International patent application no. PCT/US09/67527; International patent application no. PCT/US 10/37309; International patent application no. PCT/USlO/37316; or US Patent Application no. 12/793,440; each of which is herein incorporated by reference.
[0016] In some embodiments, the inhalable formulation comprises an LPAi and LPA3 dual antagonist. In some embodiments, the inhalable formulation comprises an LPAi and LPA2 dual antagonist. In some embodiments, the inhalable formulation comprises a selective LPAi antagonist.
[0017] In some embodiments, the inhalable formulation comprises an LPA receptor antagonist that is selected from compounds described in U.S. Patent Nos. 6,964,975; 7,288,558 and U.S. Application Publication No. 2006/0194850, or pharmaceutically acceptable salt, or N-oxide thereof.
[0018] Provided, in some embodiments, herein is a method of treating an LPA-dependent or LPA- mediated disease or condition, comprising administering to a mammal in need thereof a
therapeutically-effective amount of an inhalable formulation described herein. [0019] Also provided herein is a method of antagonizing LPA receptors in a mammal, comprising administering to the mammal an inhalable formulation described herein. In one aspect, provided herein is a method of antagonizing LPA receptors in the lungs of a mammal, comprising
administering to the mammal an inhalable formulation described herein. In one aspect, the mammal has at least one symptom of an LPA-dependent or LPA-mediated disease or condition. In one aspect, the mammal has at least one symptom of an LPA-dependent or LPA-mediated disease or condition that affects the lungs. In one aspect, the mammal is a human. In some embodiments, the method comprises administration of an inhalable formulation that is in the form of a solution, suspension, emulsion, colloidal dispersion, spray, dry powder, aerosol, or drops, or combinations thereof.
[0020] In some embodiments of the methods described herein, the LPA-dependent or LPA-mediated disease or condition is lung cancer, asthma, obstructive pulmonary disease (COPD), pulmonary fibrosis, idiopathic pulmonary fibrosis, radiation induced fibrosis, silicosis, asbestos induced pulmonary or pleural fibrosis, acute lung injury, acute respiratory distress syndrome (ARDS), usual interstitial pneumonia (UIP), cystic fibrosis, Chronic lymphocytic leukemia (CLL)-associated fibrosis, Hamman-Rich syndrome, Caplan syndrome, coal worker's pneumoconiosis, cryptogenic fibrosing alveolitis, obliterative bronchiolitis, chronic bronchitis, emphysema, Wegner's
granulamatosis, or interstitial lung disease.
[0021] In some embodiments of the methods described herein, the the LPA-dependent or LPA- mediated disease or condition is lung cancer, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), usual interstitial pneumonia (UIP), cystic fibrosis, Chronic lymphocytic leukemia (CLL)-associated fibrosis, Hamman-Rich syndrome, Caplan syndrome, coal worker's pneumoconiosis, silicosis, interstitial lung disease, asbestos induced pulmonary or pleural fibrosis, cryptogenic fibrosing alveolitis, or obliterative bronchiolitis.
[0022] In some embodiments of the methods described herein, the LPA-dependent or LPA-mediated disease or condition is idiopathic pulmonary fibrosis. In some embodiments of the methods described herein, the LPA-dependent or LPA-mediated disease or condition is cystic fibrosis. In some embodiments of the methods described herein, the LPA-dependent or LPA-mediated disease or condition is Chronic lymphocytic leukemia (CLL)-associated fibrosis. In some embodiments of the methods described herein, the LPA-dependent or LPA-mediated disease or condition is silicosis.
[0023] In some embodiments of the methods described herein, the LPA-dependent or LPA-mediated disease or condition is asthma or chronic obstructive pulmonay disease (COPD). In some
embodiments of the methods described herein, the inhalable formulation is administered before contact with an irritant and/or allergen. In some embodiments of the methods described herein, the inhalable formulation is administered after contact with an irritant and/or allergen. [0024] In some embodiments the inhalable formulation comprises at least one pharmaceutically acceptable excipient selected from pH-modifying agents, tonicity agents, propellants, preservatives, and surfactants.
[0025] In some embodiments, the inhalable formulation is administered with an atomizer, an insufflator, a nebulizer, a vaporizer, or a metered dose inhaler. In some embodiments, the inhalable formulation is inhaled nasally or orally.
[0026] In some embodiments, the inhalable formulation comprises LPA receptor antagonist(s) wherein the particle size of the LPA receptor antagonist is about 20-60 μηι in diameter.
[0027] In some embodiments, the inhalable formulation comprises LPA receptor antagonist(s) wherein the particle size of the LPA receptor antagonist is about 5-20 μηι in diameter.
[0028] Also provided herein is a method of increasing the concentration of an LPA receptor antagonist in the lungs of a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of an inhalable formulation described herein. In some embodiments, the mammal has at least one symptom of an LPA-dependent or LPA-mediated disease or condition affecting the lungs. In some embodiments, the mammal has at least one symptom of an LPAi- dependent or LPA mediated disease or condition affecting the lungs.
[0029] In some embodiments, the inhalable formulations provided herein are used to antagonize at least one LPA receptor in the lungs of a mammal in need thereof. In some embodiments, inhalable formulations provided herein are used to antagonize at least one LPA receptor for the treatment of a disease or condition that would benefit from antagonizing at least one LPA receptor in the lungs of a mammal in need thereof. In one aspect, the LPA receptor antagonized is LPAi. In one aspect the LPA receptors antagonized are LPAi and LPA3.
[0030] Articles of manufacture, which include packaging material, inhalable formulations within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, tautomers, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, used for inhibiting the activity of at least one LPA receptor, or for the treatment, prevention or amelioration of one or more symptoms of a disease or condition that would benefit from inhibition of the activity of at least one LPA receptor, are provided.
[0031] Other objects, features and advantages of the inhalable formulations described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description DETAILED DESCRIPTION OF THE INVENTION
[0032] Lysophospholipids are membrane-derived bioactive lipid mediators. Lysophospholipids include, but are not limited to, lysophosphatidic acid (l-acyl-2-hydroxy-s«-glycero-3 -phosphate; LPA), sphingosine 1 -phosphate (S IP), lysophosphatidylcholine (LPC), and
sphingosylphosphoryl choline (SPC). The lysophospho lipid LPA acts through sets of specific G protein-coupled receptors (GPCRs) in an autocrine and paracrine fashion.
[0033] LPA binding to its cognate GPCRs (LPA LPA2, LPA3, LPA4, LPA5) activates intracellular signaling pathways that mediate a variety of biological responses, including e.g., beneficial processes such as wound healing, angiogenesis, myelination, immunity and/or neurogenesis. LPA binding to its cognate GPCRs (LPAi, LPA2, LPA3, LPA4, LPA5) also plays a role in physiological pathways related to inflammation and/or carcinogenesis. The cellular responses to LPA are predominantly mediated through the lysophosphatidic acid receptors. Thus, LPA binding to LPA receptors mediates the pathology of disorders, diseases or conditions associated with, for example, aberrant wound healing, cell proliferation, block in apoptosis, and/or inflammation. LPA receptor antagonists disrupt LPA-dependent or LPA-mediated biological processes and reverse, ameliorate, prevent and/or treat LPA-dependent or LPA-mediated diseases or conditions.
[0034] Disclosed herein is the use of LPA receptor antagonists in the manufacture of medicaments suitable for inhalable administration to the lungs of a mammal for the treatment or prevention of LPA-dependent or LPA-mediated diseases, disorders or conditions. In one aspect, the LPA receptor antagonists are LPAi receptor antagonists. In one aspect, the LPA receptor antagonists are dual LPAi and LP A3 receptor antagonists. In one aspect, pulmonary administration of any inhaled formulation described herein antagonizes LPA receptors locally in the lungs.
[0035] Described herein, in certain embodiments, are inhalable formulations for administration to the lungs of a mammal that include an LPA receptor antagonist compound for treating an LPA- dependent or LPA-mediated disease, disorder or condition. In one aspect, inhalable administration of an LPA receptor antagonist compound to the lungs of a mammal minimizes systemic absorption of the LPA receptor antagonist compound. In one aspect, treatment of LPA-dependent or LPA-mediated diseases, disorders or conditions with an inhalable formulation described herein reduces possible side effects associated with systemic administration of an LPA receptor antagonist compound.
Illustrative LPA-mediated or LPA-dependent diseases or conditions
Fibrosis
[0036] Normal wound healing occurs by a highly coordinated sequence of events in which cellular, soluble factors and matrix components act in concert to repair the injury. Activated platelets play pivotal roles in wound healing processes by releasing bioactive mediators to induce cell proliferation, cell migration, blood coagulation, and angiogenesis. LPA is one such mediator that is released from activated platelets; this induces platelet aggregation along with mitogenic/migration effects on the surrounding cells, such as endothelial cells, smooth muscle cells, fibroblasts, and keratinocytes.
[0037] LPA regulates many important functions of fibroblasts in wound healing, including proliferation, migration, differentiation and contraction. Fibroblast proliferation is required in wound healing in order to fill an open wound. In contrast, fibrosis is characterized by intense proliferation and accumulation of myofibroblasts that actively synthesize ECM and proinflammatory cytokines. LPA can either increase or suppress the proliferation of cell types important in wound healing, such as epithelial and endothelial cells (EC),macrophages, keratinocytes, and fibroblasts. A role for LPAi in LPA-induced proliferation was provided by the observation that LPA-stimulated proliferation of fibroblasts isolated from LPAi receptor null mice was attenuated (Mills et al, Nat Rev. Cancer 2003; 3: 582-591). LPA induces cytoskeletal changes that are integral to fibroblast adhesion, migration, differentiation and contraction.
[0038] Tissue injury initiates a complex series of host wound-healing responses; if successful, these responses restore normal tissue structure and function. Aberrant responses can lead to tissue fibrosis and loss of function.
[0039] In the lung, aberrant wound healing responses to injury contribute to the pathogenesis of fibrotic lung diseases. Fibrotic lung diseases, such as idiopathic pulmonary fibrosis (IPF), are associated with high morbidity and mortality.
[0040] In some instances aberrant LPAi -receptor stimulation in the lung causes vascular leakage and increased fibroblast recruitment, both profibrotic events. Thus the LP A- LPAi pathway has a role in mediating fibroblast migration and vascular leakage in IPF. The end result is an aberrant healing process and consequent fibrosis.
[0041] The LPAi receptor is the LPA receptor most highly expressed on fibroblasts obtained from patients with IPF. In human subjects with IPF, high LPA levels are observed in bronchoalveolar lavage samples compared with healthy controls. The LP A- LPAi pathway is crucial in fibroblast recruitment and vascular leakage in pulmonary fibrosis. In certain instances, treatment of IPF and other fibrotic conditions with an LPA receptor antagonist reverses the profibrotic aberrant wound healing processes.
[0042] The terms "fibrosis" or "fibrosing disorder," as used herein, refers to conditions that are associated with the abnormal accumulation of cells and/or fibronectin and/or collagen and/or increased fibroblast recruitment and include but are not limited to fibrosis of individual organs or tissues such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and digestive tract.
[0043] Exemplary diseases, disorders, or conditions that involve fibrosis include, but are not limited to: Lung diseases associated with fibrosis, e.g., lung cancer, asthma, obstructive pulmonary disease (COPD), pulmonary fibrosis, idiopathic pulmonary fibrosis, radiation induced fibrosis, silicosis, asbestos induced pulmonary or pleural fibrosis, acute lung injury, acute respiratory distress syndrome (ARDS, including bacterial pneumonia induced, trauma induced, viral pneumonia induced, ventilator induced, non-pulmonary sepsis induced, and aspiration induced), usual interstitial pneumonia (UIP), cystic fibrosis, Chronic lymphocytic leukemia (CLL)-associated fibrosis, Hamman-Rich syndrome, Caplan syndrome, coal worker's pneumoconiosis, cryptogenic fibrosing alveolitis, obliterative bronchiolitis, chronic bronchitis, emphysema, Wegner's granulamatosis, or interstitial lung disease.
[0044] In certain instances, the inhalable formulations described herein are used in the treatment of various fibroses associated with LPA-mediated or LPA-dependent aberrant wound healing and/or fibrosis in a mammal. In some embodiments, the inhalable formulations described herein are administered to the lungs of a mammal and antagonize LPA receptors in the lungs of the mammal. In some instances, antagonizing LPA receptors that are associated with aberrant wound healing and/or fibrosis reduces or inhihbits the proliferation of fibroblasts and/or increases apoptosis of fibroblasts associated with fibrotic disorders. In one aspect the inhalable formulations described herein reduce, ameliorate or inhibit aberrant wound healing, fibroblast proliferation and/or fibrosis associated with LPA-dependent or LPA-mediated fibrotic disorders. In one aspect, the LPA receptors are LPAi and/or LP A3 receptors. In one aspect, the LPA receptors are LPAi and/or LPA2 receptors.
[0045] In one aspect, the inhalable formulations described herein are used in the treatment of lung diseases associated with fibrosis in a mammal. In one aspect, the inhalable formulations described herein are used in the treatment of pulmonary fibroses in a mammal. In one aspect, the inhalable formulations described herein are used in the treatment of lung cancer, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), usual interstitial pneumonia (UIP), cystic fibrosis, Chronic lymphocytic leukemia (CLL)-associated fibrosis, Hamman-Rich syndrome, Caplan syndrome, coal worker's pneumoconiosis, silicosis, interstitial lung disease, asbestos induced pulmonary or pleural fibrosis, cryptogenic fibrosing alveolitis, or obliterative bronchiolitis in a mammal.
[0046] In one aspect, the inhalable formulations described herein are adminstered to a mammal with pulmonary fibrosis or with a predisposition of developing pulmonary fibrosis in combination with one or more other agents that are used to treat fibrosis. In one aspect, the one or more agents include corticosteroids. In one aspect, the one or more agents include immunosuppresants. In one aspect, the one or more agents include B-cell antagonists. In one aspect, the one or more agents include uteroglobin.
[0047] In some embodiments, provided is a method of reducing lung injury, vascular leakage, inflammation and/or fibrosis in a mammal comprising administering to the mammal an inhalable formulation that includes at least one LPA receptor antagonist. In some embodiments, provided is a method of reducing lung injury, vascular leakage, inflammation and pulmonary fibrosis in a mammal comprising administering to the mammal an inhalable formulation that includes at least one LPA receptor antagonist. In some embodiments, provided is a method of attenuating pulmonary fibrosis in a mammal comprising administering to the mammal an inhalable formulation that includes at least one LPA receptor antagonist. In some embodiments, provided is a method of attenuating tissue remodeling and fibrosis in the lungs of a mammal comprising administering to the mammal an inhalable formulation that includes at least one LPA receptor antagonist.
[0048] In some embodiments, provided is a method of decreasing cytokine production in a mammal comprising administering to the mammal an inhalable formulation that includes at least one LPA receptor antagonist. In some embodiments, the method of decreasing cytokine production in a mammal comprising administering to the mammal an inhalable formulation that includes at least one LPA receptor antagonist results in a reduction of tissue damage and fibrosis in the lungs of the mammal.
[0049] In some embodiments, provided is a method of treating pulmonary fibrosis in a mammal comprising administering to the mammal an inhalable formulation that includes at least one LPA receptor antagonist. In some embodiments, provided is a method of treating fibrosis in a mammal while maintaining body weight in the mammal comprising administering to the mammal an inhalable formulation that includes at least one LPA receptor antagonist. In some embodiments, provided is a method of treating respiratory disease in a mammal comprising administering to the mammal an inhalable formulation that includes at least one LPA receptor antagonist.
[0050] In some embodiments, provided is a method of treating fibrosis in a mammal comprising administering to the mammal an inhalable formulation that includes at least one LPA receptor antagonist, wherein the fibrosis in the mammal is not responsive to treatment with pirfenidone.
[0051] In some embodiments, provided is a method of controlling an abnormal accumulation or activation of cells, fibronectin, collagen or increased fibroblast recruitment in lung tissues of a mammal comprising administering to the mammal an inhalable formulation that includes at least one LPA receptor antagonist.
[0052] In some embodiments, the abnormal accumulation or activation of cells, fibronectin, collagen or increased fibroblast recruitment in the tissue results in pulmonary fibrosis.
Respiratory and Allergic Disorders
[0053] In one aspect, LPA is a contributor to the pathogenesis of respiratory diseases. In one aspect the respiratory disease is asthma. Proinflammatory effects of LPA include degranulation of mast cells, contraction of smooth-muscle cells and release of cytokines from dendritic cells. Airway smooth muscle cells, epithelial cells and lung fibroblasts all show responses to LPA. The release of LPA from platelets activated at a site of injury and its ability to promote fibroblast proliferation and contraction are features of LPA as a mediator of wound repair. In the context of airway disease, asthma is an inflammatory disease where inappropriate airway "repair" processes lead to structural "remodeling" of the airway. In asthma, the cells of the airway are subject to ongoing injury due to a variety of insults, including allergens, pollutants, other inhaled environmental agents, bacteria and viruses, leading to the chronic inflammation that characterizes asthma.
[0054] In one aspect, in the asthmatic individual, the release of normal repair mediators, including LPA, is exaggerated or the actions of the repair mediators are inappropriately prolonged leading to inappropriate airway remodeling. Major structural features of the remodeled airway observed in asthma include a thickened lamina reticularis (the basement membrane-like structure just beneath the airway epithelial cells), increased numbers and activation of myofibroblasts, thickening of the smooth muscle layer, increased numbers of mucus glands and mucus secretions, and alterations in the connective tissue and capillary bed throughout the airway wall. In one aspect, LPA contributes to these structural changes in the airway. In one aspect, LPA is involved in acute airway
hyperresponsiveness in asthma. The lumen of the remodeled asthmatic airway is narrower due to the thickening of the airway wall, thus decreasing airflow. In one aspect, LPA contributes to the long- term structural remodeling and the acute hyperresponsiveness of the asthmatic airway. In one aspect, LPA contributes to the hyper-responsiveness that is a primary feature of acute exacerbations of asthma.
[0055] In one aspect, the fibroblast proliferation and contraction and extracellular matrix secretion stimulated by LPA contributes to the fibroproliferative features of other airway diseases, such as the peribronchiolar fibrosis present in chronic bronchitis, emphysema, and interstitial lung disease.
Emphysema is also associated with a mild fibrosis of the alveolar wall, a feature which is believed to represent an attempt to repair alveolar damage. In another aspect, LPA plays a role in the fibrotic interstitial lung diseases and obliterative bronchiolitis, where both collagen and myofibroblasts are increased. In another aspect, LPA is involved in several of the various syndromes that constitute chronic obstructive pulmonary disease.
[0056] Administration of LPA in vivo induces airway hyper-responsiveness, itch-scratch responses, infiltration and activation of eosinophils and neutrophils, vascular remodeling, and nociceptive flexor responses. LPA also induces histamine release from mast cells. In an acute allergic reaction, histamine induces various responses, such as contraction of smooth muscle, plasma exudation, and mucus production. Plasma exudation is important in the airway, because the leakage and subsequent airway-wall edema contribute to the development of airway hyperresponsiveness. Plasma exudation progresses to conjunctival swelling in ocular allergic disorder and nasal blockage in allergic rhinitis (Hashimoto et ah, J Pharmacol Sci 100, 82 - 87, 2006). In one aspect, plasma exudation induced by LPA is mediated by histamine release from mast cells via one or more LPA receptors. In one aspect, the LPA receptor(s) include LPAi and/or LP A3.
[0057] The term "respiratory disease," as used herein, refers to diseases affecting the organs that are involved in breathing, such as the nose, throat, larynx, eustachian tubes, trachea, bronchi, lungs, related muscles (e.g., diaphram and intercostals), and nerves. Respiratory diseases include, but are not limited to, asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen- induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, child- onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, including chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation and cystic fibrosis, and hypoxia.
[0058] The term "asthma" as used herein refers to any disorder of the lungs characterized by variations in pulmonary gas flow associated with airway constriction of whatever cause (intrinsic, extrinsic, or both; allergic or non-allergic). The term asthma may be used with one or more adjectives to indicate cause.
[0059] In one aspect, the inhalable formulations described herein are used in the treatment of various allergic disorders in a mammal. In one aspect, the inhalable formulations described herein are administered to the lungs of a mammal and antagonize LPA receptors. In some instances, antagonizing LPA receptors associated with airway remodeling reduces or inhihbits the proliferation of fibroblasts and/or increases apoptosis of fibroblasts associated with airway remodeling that is associated with allergic disorders. In one aspect the inhalable formulations described herein reduce, ameliorate or inhibit inflammation, airway remodeling and/or fibrosis associated with LPA- dependent or LPA-mediated allergic disorders. In one aspect, the LPA receptors are LPAi and/or LPA3 receptors.
[0060] In one aspect, the inhalable formulations described herein are used in the treatment of respiratory diseases, disorders or conditions in a mammal. In one aspect, the inhalable formulations described herein are used in the treatment of asthma in a mammal. In one aspect, the inhalable formulations described herein are used in the treatment of chronic asthma in a mammal. In some instances, the inhalable formulations described herein are used in the treatment of acute respiratory distress syndrome (ARDS, including bacterial pneumonia induced, trauma induced, viral pneumonia induced, ventilator induced, non-pulmonary sepsis induced, and aspiration induced) in a mammal. In one aspect, the inhalable formulations described herein are used in the treatment of chronic obstructive pulmonay disease in a mammal. Chronic obstructive pulmonary disease includes, but is not limited to, chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation, and cystic fibrosis.
Cancer
[0061] Lysophospholipid receptor signaling plays a role in the etiology of cancer. Lysophosphatidic acid (LPA) and its G protein-coupled receptors (GPCRs) LPAl5 LPA2, and/or LPA3 play a role in the development of several types of cancers. The initiation, progression and metastasis of cancer involve several concurrent and sequential processes including cell proliferation and growth, survival and anti- apoptosis, migration of cells, penetration of foreign cells into defined cellular layers and/or organs, and promotion of angiogenesis.
[0062] LPA signals through its own GPCRs leading to activation of multiple downstream effector pathways. Such downstream effector pathways play a role in cancer. LPA and its GPCRs are linked to cancer through major oncogenic signaling pathways. LPA contributes to tumorigenesis by increasing motility and invasiveness of cells. Mutations of LPAi gene are involved in the acquisition of growth advantage and progression of adenomas to adenocarcinomas in lung cancer (Biochem Biophys Res Commun. 2009, 378(3):424-7). LPA reduces the cellular abundance of the tumor suppressor p53 in A549 lung carcinoma cells, which express endogenous LPA receptors {Mol Cancer Res. 2007 5(11): 1201-11). The suppresion of p53 by LPA stimulates cancer cell division, protects against apoptosis, and thereby promotes tumor progression.
[0063] Airway and lung inflammation is a serious problem faced by Chronic Lymphocytic Leukemia (CLL) patients. CLL is characterized by the accumulation of CD19+/CD5+ B-lymphocytes primarily through a block in apoptosis. In B-cells, LPA acts as a growth factor promoting cell proliferation. LPA also contributes to VEGF production in B cell malignancies leading to cell survival. In addition, LPA protects epithelial and fibroblast cell lines from apoptosis. LPAi expression is increased in primary CLL cells compared with normal B-cells (J. Biol. Chem. 2005, 280, 9498-9508). Treatment of primary CLL cells with an LPA receptor antagonist reverses the protective effect of LPA against apoptosis and provides effective therapy against B-cell derived malignancies such as CLL.
[0064] In one aspect, the inhalable formulations described herein are used in the treatment of lung cancer and/or fibrosis associated with lung cancer. In one aspect, the inhalable formulations described herein are used in the treatment of lung cancer. In one aspect, the inhalable formulations described herein are administered to the lungs of a mammal and antagonize LPA receptors associated with cell proliferation. In some instances, antagonizing LPA receptors associated with cell proliferation reduces or inhibits the proliferation of fibroblasts and/or B-cells and/or increases apoptosis of fibroblasts and/or B-cells associated with lung cancer and/or fibrosis associated with lung cancer. In one aspect the inhalable formulations described herein reduce, ameliorate or inhibit cell proliferation and/or fibrosis associated with LPA-dependent or LPA-mediated cancers. In one aspect, the LPA receptors are LPAi and/or LPA3 receptors.
[0065] The term "cancer," as used herein refers to an abnormal growth of cells which tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread). The type of cancer includes, but is not limited to, solid tumors, melanoma or basal cell cancer or hematological tumors (such as the leukemias) at any stage of the disease with or without metastases.
[0066] In some instances the lung cancer is non-small cell lung cancer. In some embodiments, the lung cancer is an adenocarcinoma. In some embodiments, the inhalable formulations described herein are used in the treatment of B-cell derived malignancies (e.g., CLL) and/or CLL-associated fibrosis.
Inflammation
[0067] LPA has been shown to regulate immunological responses by modulating activities/functions of immune cells such as T-/B-lymphocytes and macrophages. In activated T cells, LPA activates IL-2 production/cell proliferation through LPAi. Expression of LPA-induced inflammatory response genes is mediated by LPAi and LPA3. In addition, LPA modulates the chemotaxis of inflammatory cells. The proliferation and cytokine-secreting activity in response to LPA of immune cells, platelet aggregation activity in response to LPA, acceleration of migration activity in monocytes, activation of NF-KB in fibroblast, enhancement of fibronectin-binding to the cell surface, and the like are known. Thus, LPA is associated with various inflammatory/immune diseases .
[0068] In one aspect, an inhalable formulation that includes at least one LPA receptor antagonist is used to treat or prevent inflammation in a mammal. In one aspect, an inhalable formulation that includes at least one LPA receptor antagonist is used to treat or prevent inflammation of the lungs in a mammal. In one aspect, an inhalable formulation that includes at least one LPA receptor antagonist finds use in the treatment or prevention of inflammatory/immune disorders that affect lung tissues in a mammal.
[0069] Examples of inflammatory/immune disorders include, but are not limited to, asthma, allergic rhinitis, pulmonary fibrosis, cystic fibrosis.
Other Diseases, Disorders or Conditions
[0070] In accordance with one aspect, are methods for treating, preventing, reversing, halting or slowing the progression of LPA-dependent or LPA-mediated diseases or conditions of the lung once it becomes clinically evident, or treating the symptoms associated with or related to LPA-dependent or LPA-mediated diseases or conditions of the lung, by administering to the mammal an inhalable formulation that includes at least one LPA receptor antagonist. In certain embodiments, the subject already has a LPA-dependent or LPA-mediated disease or condition of the lung at the time of administration, or is at risk of developing a LPA-dependent or LPA-mediated disease or condition of the lung.
[0071] In certain aspects, are methods for preventing or treating eosinophil and/or basophil and/or dendritic cell and/or neutrophil and/or monocyte and/or T-cell recruitment comprising administering at least once to the mammal an inhalable formulation that includes at least one LPA receptor antagonist.
[0072] In accordance with one aspect, methods described herein include the diagnosis or
determination of whether or not a patient is suffering from a LPA-dependent or LPA-mediated disease or condition of the lungs by administering to the subject an inhalable formulation that includes at least one LPA receptor antagonist and determining whether or not the patient responds to the treatment.
[0073] In certain aspects, the activity of LPAi in a mammal is directly or indirectly modulated by the administration of (at least once) an inhalable formulation that includes at least one LPA receptor antagonist. Such modulation includes, but is not limited to, reducing and/or inhibiting the activity of LPAi. In additional aspects, the activity of LPA in a mammal is directly or indirectly modulated, including reducing and/or inhibiting, by the administration of (at least once) a therapeutically effective amount of an inhalable formulation described herein. Such modulation includes, but is not limited to, reducing and/or inhibiting the activity of an LPA receptor. In one aspect, the LPA receptors are LPAi and/or LPA3 receptors. In one aspect, the LPA receptors are LPAi and/or LPA2 receptors.
[0074] Also provided is a method of inhibiting the physiological activity of LPA in a mammal comprising administering to the mammal an inhalable formulation that includes at least one LPA receptor antagonist.
[0075] In one aspect, provided is a medicament for treating a LPA-dependent or LPA-mediated disease or condition in a mammal comprising a therapeutically effective amount of an LPA antagonist.
[0076] In some cases disclosed herein is the use of an inhalable formulation that includes at least one LPA receptor antagonist in the treatment or prevention of a LPA-dependent or LPA-mediated disease or condition.
[0077] In one aspect, is a method for treating or preventing a LPA-dependent or LPA-mediated disease or condition in a mammal comprising administering administering to the mammal an inhalable formulation that includes at least one LPA receptor antagonist.
[0078] In one aspect, LPA-dependent or LPA-mediated diseases or conditions include, but are not limited to, fibrosis involving the lungs, cancer involving the lungs, cardiovascular disease, respiratory diseases or conditions, inflammatory disease.
[0079] In one aspect, the LPA-dependent or LPA-mediated disease or condition is a respiratory disease or condition. In some embodiments, the respiratory disease or condition is asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pulmonary arterial hypertension or acute respiratory distress syndrome.
[0080] In some embodiments, the LPA-dependent or LPA-mediated disease or condition is selected from idiopathic pulmonary fibrosis; other diffuse parenchymal lung diseases of different etiologies including iatrogenic drug-induced fibrosis, occupational and/or environmental induced fibrosis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonia), collagen vascular disease, alveolar proteinosis, langerhans cell granulomatosis, lymphangioleiomyomatosis, inherited diseases
(Hermansky-Pudlak Syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage disorders, familial interstitial lung disease); radiation induced fibrosis; chronic obstructive pulmonary disease (COPD); bleomycin induced pulmonary fibrosis; chronic asthma; silicosis; asbestos induced pulmonary fibrosis; lung scleroderma; acute respiratory distress syndrome (ARDS); neonatal respiratory distress syndrome.
[0081] In one aspect, the LPA-dependent or LPA-mediated disease or condition is described herein.
[0082] In one aspect, provided is a method of improving lung function in a mammal comprising administering to the mammal an inhalable formulation that includes at least one LPA receptor antagonist. In one aspect, the mammal has been diagnosed as having lung fibrosis.
[0083] In one aspect, inhalable formulations that includes at least one LPA receptor antagonist are used to treat idiopathic pulmonary fibrosis (usual interstitial pneumonia) in a mammal.
[0084] In some embodiments, inhalable formulations that includes at least one LPA receptor antagonist are used to treat post-transplant fibrosis associated with chronic rejection in a mammal: Bronchiolitis obliterans for lung transplant.
[0085] In some embodiments, inhalable formulations that includes at least one LPA receptor antagonist are used for inhibiting the activity of at least one LPA receptor in the lungs of a mammal or for the treatment of a disease or condition affecting the pulmonary system (i.e. lungs) that would benefit from inhibition of the activity of at least one LPA receptor in the lungs of the lungs of the mammal. In one aspect, the LPA receptor is LPAi.
Compounds
[0086] In one aspect, an LPA receptor antagonist is selected from LPA receptor antagonists described herein or known in the art. In one aspect, the LPA receptor antagonist is an LPAi selective antagonist. In another aspect, the LPA antagonist is an LPAi and LPA3 dual antagonist. In another aspect, the LPA antagonist is an LPAi and LPA2 dual antagonist.
[0087] In certain aspects, the activity of LPA in a mammal is directly or indirectly modulated by the administration of (at least once) a therapeutically effective amount of an LPA receptor antagonist. Such modulation includes, but is not limited to, reducing and/or inhibiting the activity of LPAi. In additional aspects, the activity of LPA in a mammal is directly or indirectly modulated, including reducing and/or inhibiting, by the administration of (at least once) a therapeutically effective amount of an LPA receptor antagonist. Such modulation includes, but is not limited to, reducing and/or inhibiting the activity of an LPA receptor. In one aspect, the LPA receptors are LPAi and/or LP A3 receptors. In one aspect, the LPA receptors are LPAi and/or LPA2 receptors.
[0088] LPA receptor antagonists are disclosed herein or in any one of the following: US Provisional Application no. 61/122,568; US Provisional Application no. 61/183,785; US Patent Application no. 12/638,702; US Provisional Application no. 61/121,862; US Provisional Application no. 61/231,282; US Provisional Application no. 61/247,681; US Provisional Application no. 61/2472877;
International patent application no. PCT/US2010/44284; International patent application no. PCT/US2010/51199; International patent application no. PCT/US2010/51150; US Patent Application no. 12/896,080; International patent application no. PCT/US2010/50786; International patent application no. PCT/US2010/50787; US Patent Application no. 12/893,902; International patent application no. PCT/US09/68106; International patent application no. PCT/US09/68105;
International patent application no. PCT/US09/67527; International patent application no.
PCT/US 10/37309; International patent application no. PCT/US 10/37316; US Patent Application no. 12/793,440; each of which is herein incorporated by reference.
[0089] In some embodiments, the LPA receptor antagonist has the structure of Formula (I):
Figure imgf000017_0001
Formula (I)
wherein,
Pv1 is -C02H, -C02RD, tetrazolyl, 5-oxo-2,5-dihydro-[l,2,4]oxadiazol-3-yl, -
C(=0)NHS02CH3, or -C(=0)NHS02CH2CH3; RDis -CH3, -CH2CH3, -CH2CH2CH3, - CH(CH3)2, -CH2CH2CH2CH3, or -C(CH3)3;
L1 is Ci-C4alkylene or C3-C6cycloalkylene;
Pv3 is H, -CH3, -CH2CH3, or -CF3;
Figure imgf000017_0002
CY is Ci-C6alkyl, substituted or unsubstituted C3-C6cycloalkyl, or substituted or
unsubstituted phenyl; wherein if CY is substituted then CY is substituted with 1 or 2 Rc; each Rc is independently F, CI, Br, I, -OH, -CN, d-C4alkyl, Ci-C4fluoroalkyl, C
C4fluoroalkoxy, or Ci-C4alkoxy;
or a pharmaceutically acceptable salt, prodrug, active metabolite, or a pharmaceutically
acceptable solvate thereof.
[0090] In some embodiments, CY is substituted or unsubstituted phenyl; wherein if CY is substituted then CY is substituted with 1 or 2 Rc; each Rc is independently F, CI, -CN, -CH3, -CF3, -OH, -OCF3,
or -OCH3. In some embodiments, CY is
Figure imgf000017_0003
; n is 0, 1, or 2. In some embodiments, n is 0 or
1. In some embodiments, CY is cyclopropyl, cyclobutyl, cyclopentyl, cyclopent-l-enyl, 2- chlorocyclopent-l-enyl, cyclohexyl, cyclohex- 1 -enyl, 2-chlorocyclohex-l-enyl, phenyl, 2- fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2- chlorophenyl, 2,6-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 2,4-dichlorophenyl, 2- hydroxyphenyl, 3-hydroxyphenyl, 4- hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4- methoxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2- fluoro-4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-cyanophenyl, 3- cyanophenyl, or 4-cyanophenyl. In some embodiments, CY is phenyl, 2-fluorophenyl, 2- chlorophenyl, 2-trifluoromethylphenyl, or 2-methylphenyl. In some embodiments, CY is phenyl, 2- fluorophenyl, or 2-chlorophenyl. In some embodiments, CY is phenyl.
[0091] In some embodiments, the compound of Formula (I) has the following structure:
Figure imgf000018_0001
[0092] In some embodiments the LPA receptor antagonist has the structure of Formula (II):
Figure imgf000018_0002
Formula (II).
[0093] In some embodiments, R1 is -CO2H. In some embodiments, L1 is -CH2-, -CH2CH2-, - CH2CH2CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CH2CH3)-, -C(CH2CH3)2-, -CH2CH(CH3)-, -CH2C(CH3)2- , cyclopropyl- 1,1 -diyl, cyclopropyl- 1,2-diyl, cyclobutyl- 1,1 -diyl, cyclopentyl- 1,1 -diyl or cyclohexyl - 1,1 -diyl. In some embodiments, L1 is -CH2-, -C(CH3)2-, or -C(CH2CH3)2-. In some embodiments, L is -CH2- or cyclopropyl- 1 , 1 -diyl. In some embodiments, L1 is -CH2-. In some embodiments, L1 is cyclopropyl- 1 , 1 -diyl, cyclobutyl- 1 , 1 -diyl, cyclopentyl- 1 , 1 -diyl or cyclohexyl- 1 , 1 -diyl. In some embodiments, L1 is cyclopropyl- 1 , 1 -diyl. In some embodiments, R3 is H. In some embodiments, R3 is -CH3. In some embodiments, each of Rc is independently selected from F, CI, -CH3, and -CF3; n is 0 or 1.
[0094] In some embodiments, the LPA receptor antagonist is selected from:
[0095] (R)-2-(4'-(3-methyl-4-((l-phenylethoxy)carbonylamino)isoxazol-5-yl)biphenyl-4-yl)acetic acid (Compound A): N H HO
Figure imgf000019_0001
[0096] (R)-l-(4'-(3-methyl-4-((l-phenylethoxy)carbonylamino)isoxazol-5-yl)biphenyl-4- yl)cyclopropanecarboxylic acid (Compound B):
Figure imgf000019_0002
[0097] (R)-2-(4'-(4-((l-(2-chlorophenyl)ethoxy)carbonylamino)-3-methylisoxazol-5-yl)biphi yl)acetic acid (Compound C):
Figure imgf000019_0003
[0098] {5-[4'-(l-Methanesulfonylaminocarbonyl-cyclopropyl)-biphenyl-4-yl]-3-methyl-isoxazol-4- yl}-carbamic acid (R)- 1 -phenyl- thyl ester (Compound D):
Figure imgf000019_0004
[0099] 1 -(4'- (4-[(R)- 1 -(2-Chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl} -biphenyl- 4-yl)-cyclopropanecarboxylic acid (Compound E):
Figure imgf000020_0001
[00100] l-{4'-[4-((R)-l-Phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}- cyclopropanecarboxylic acid (Compound F):
Figure imgf000020_0002
[00101] (3-Methyl-5-{4'-[l-(5-oxo-2,5-dihydro-[l,2,4]oxadiazol-3-yl)-cyclopropyl]-biphi isoxazol-4-yl)-carbamic acid (R - 1 -phenyl-ethyl ester (Compound G):
Figure imgf000020_0003
[00102] (3-Methyl-5-{4'-[l-(lH-tetrazol-5-yl)-cyclopropyl]-biphenyl-4-yl}-isoxazol-4-yl)-carbamic acid (R)- 1 -phenyl-ethyl ester (Compound Η):
Figure imgf000020_0004
[00103] In some embodiments, the LPA receptor antagonist has structure of Formula (III):
Figure imgf000021_0001
Formula (III)
wherein,
R1 is -C02H, -C02RD, tetrazolyl, 5-oxo-2,5-dihydro-[l,2,4]oxadiazol-3-yl, - C(=0)NHS02CH3, or -C(=0)NHS02CH2CH3; RD is -CH3, -CH2CH3, -CH2CH2CH3, -
CH(CH3)2, -CH2CH2CH2CH3, or -C(CH3)3;
L1 is absent, or a Ci-C6alkylene;
R3 is H, -CH3, -CH2CH3, or -CF3;
R4 is -NHC(=0)OCH(R8)-CY;
R8 is H, or -CH3;
CY is substituted or unsubstituted phenyl; wherein if CY is substituted then CY is
substituted with 1 or 2 Rc; each Rc is independently F, CI, Br, I, -OH, -CN, C
C4alkyl, Ci-C4fluoroalkyl, Ci-C4fluoroalkoxy, or C C4alkoxy;
or a pharmaceutically acceptable salt, prodrug, active metabolite, or a pharmaceutically
acceptable solvate thereof.
[00104] In some embodiments, R1 is -C02H or -C02RD. In some embodiments, R1 is -C02H. In some embodiments, L1 is -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -
CH2CH2CH2-, or -CH2CH2CH2CH2-. In some embodiments, L1 is -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-. In some embodiments, L1 is -CH2CH2CH2-, or -CH2CH2CH2CH2-. In some embodiments, R3 is H. In some embodiments, R3 is -CH3. In some embodiments, R8 is -CH3. In some embodiments, each of Rc is independently selected from F, CI, -CH3, and -CF3.
[00105] In some embodiments, R4 is
Figure imgf000021_0002
[00106] In some embodiments, CY is a substituted or unsubstituted phenyl, wherein if CY is substituted then CY is substituted with 1 or 2 Rc; each Rc is independently F, CI, -CN, -CH3, -CF3, - OH, -OCF3, or -OCH3.
[00107] In some embodiments, the LPAl antagonist is selected from: 6-(4-{4-[l-(2-Chloro-phenyl)- ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-phenyl)-hex-5-ynoic acid, 7-(4-{4-[l-(2-chloro- phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-phenyl)-hept-6-ynoic acid, or a
pharmaceutically acceptable salt, prodrug, active metabolite, or a pharmaceutically acceptable solvate thereof
[00108] In some embodiments, the LPA receptor antagonist has the structure of Formula (IV):
Figure imgf000022_0001
Formula (IV)
wherein,
A is an aryl or heteroaryl ring;
R3 is H, Ci-C4alkyl, Ci-C4fluoroalkyl;
R4 is -NHC(=0)OCH(R8)-CY, or -NHC(=0)0-CY;
R8 is H, C C4alkyl, C C4fluoroalkyl;
CY is a substituted or unsubstituted C3-C6cycloalkyl, a substituted or unsubstituted
phenyl, or a substituted or unsubstituted monocyclic heteroaryl; wherein if CY is substituted then CY is substituted with 1 or 2 Rc; each Rc is independently selected from F, CI, Br, I, -CN, -OH, C C4alkyl, Ci-C4fluoroalkyl, Ci-C4fluoroalkoxy, C C4alkoxy, and Ci-C4heteroalkyl;
R5 and R6 are each independently selected from H, halogen, -CN, -N02, -OH, -OR10, C
C4alkyl, Ci-C4fluoroalkyl, Ci-C4fluoroalkoxy, Ci-C4alkoxy, and Ci-C4heteroalkyl;
R10 is selected from Ci-C6alkyl, Ci-C6heteroalkyl, Ci-C6fluoroalkyl, a substituted or
unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl;
or a pharmaceutically acceptable salt, prodrug, active metabolite, or a pharmaceutically
acceptable solvate thereof.
[00109] In some embodiments, A is phenyl, or a 5- or 6-membered monocyclic heteroaryl. In some embodiments, A is a phenyl, pyridinyl, thiazolyl, or pyrimidinyl. In some embodiments, R5 and R6 are each independently selected from hydrogen, halogen, or hydroxy. In some embodiments, R3 is methyl, ethyl, isopropyl or trifluoromethyl. In some embodiments, R3 is methyl. In some
embodiments, CY is a substituted or unsubstituted CYcycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; or
[00110] In some embodiments, the LPA1 antagonist has one of the following structures:
Figure imgf000023_0001
Figure imgf000023_0002
or a pharmaceutically acceptable salt, prodrug, active metabolite, or a pharmaceutically acceptable solvate thereof.
[00111] In some embodiments, the LPA receptor antagonist has the structure of Formula (V):
Figure imgf000023_0003
Formula (V)
wherein,
A is an aryl or heteroaryl ring;
B is an aryl or heteroaryl ring;
L is absent, C C4alkylene, C C4heteroalkylene, -0-, -S-, -SO-, -S02-, -NH-, -NR2-, or -
C(=0)-; R2 is CrQalkyl;
R3 is H, C C4alkyl, or Ci-C4fluoroalkyl;
R4 is -NHC(=0)OCH(R8)-CY, or -NHC(=0)0-CY;
R8 is H, C C4alkyl, or C C4fiuoroalkyl;
CY is a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; wherein if CY is substituted then CY is substituted with 1 or 2 Rc; each Rc is independently selected from F, CI, Br, I, -CN, -OH, C C4alkyl, C C4fluoroalkyl, Ci-C4fluoroalkoxy, Ci-C4alkoxy, and Ci-C4heteroalkyl; R5 and R6 are each independently selected from H, halogen, -CN, -N02, -OH, -OR10, C
C4alkyl, Ci-C4fluoroalkyl, Ci-C4fluoroalkoxy, Ci-C4alkoxy, and Ci-C4heteroalkyl;
R5a and R6a are each independently selected from H, halogen, -CN, -N02, -OH, -OR10, -
S(=0)2R10, substituted or unsubstituted Ci-C4alkyl, Ci-C4fluoroalkyl, Ci-C4fluoroalkoxy,
Ci-C4alkoxy, Ci-C4heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl or substituted or unsubstituted Ci-C6heterocycloalkyl; R is selected from Ci-C6alkyl, Ci-C6heteroalkyl, Ci-C6fluoroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl;
or a pharmaceutically acceptable salt, prodrug, active metabolite, or a pharmaceutically
acceptable solvate thereof.
[00112] In some embodiments, rin A is a substituted or unsubstituted monocyclic ring wherein the
groups
Figure imgf000024_0001
a 1,3 -relationship on ring A (i.e. an meta relationship).
[00113] In some embodiments, rin A is a substituted or unsubstituted monocyclic ring wherein the
groups
Figure imgf000024_0002
a 1 ,4-relationship on ring A (i.e. an para relationship).
[00114] In some embodiments, A is a phenyl ring. In some embodiments, A is a monocyclic heteroaryl. In some embodiments, A is a 6-membered monocyclic heteroaryl. In some
embodiments, A is a pyridinyl ring. In some embodiments, L is absent and A-L-B is biphenyl. In some embodiments, B is a phenyl ring. In some embodiments, B is a monocyclic heteroaryl. In some embodiments, B is a 6-membered monocyclic heteroaryl. In some embodiments, B is a pyridinyl ring. In some embodiments, A-L-B is phenyl-pyridyl. In some embodiments, R5 and R6 are each independently selected from hydrogen, halogen, or hydroxy. In some embodiments, R5a and R6a are each independently selected from hydrogen, halogen, hydroxy, hydroxymethyl or substituted or unsubstituted heterocycloalkyl. In some embodiments, R3 is methyl, ethyl, isopropyl or
trifluoromethyl.
[00115] In some embodiments, L is absent, -CH2-, -CH20-, -OCH2-, -CH2S-, -SCH2-, -CH2NH-, - NHCH2-, -0-, -S-, or -NH-. In some embodiments, L2 is absent.
[00116] In some embodiments, the LPA1 antagonist has a structure selected from:
Figure imgf000025_0001
— V ; or a pharmaceutically acceptable salt, prodrug, active metabolite, or pharmaceutically acceptable solvate thereof.
[00117] In some embodiments, the LPA receptor antagonist has the structure of Formula (VI) or a pharmaceutically acceptable salt thereof:
Figure imgf000025_0002
Formula (VI)
wherein, R1 is -C02RD, -C(=0)NHS02RE, -C(=0)N(RD)2, or tetrazolyl;
RD is H or Ci-C6alkyl;
RE is Ci-C6alkyl, C3-C6cycloalkyl, or substituted or unsubstituted phenyl;
L3 is a substituted or unsubstituted C3-C6alkylene, a substituted or unsubstituted C3- C6fluoroalkylene, or a substituted or unsubstituted C3-C6heteroalkylene, where if L3 is substituted then L3 is substituted with 1, 2 or 3 R13; each R13 is independently F, C C4alkyl, Ci-C4fluoroalkyl, or -OH;
each Rc is independently halogen, -CN, -N02, -OH, Ci-C4alkyl, Ci-C4fluoroalkyl, Ci- C4fluoroalkoxy, C C4alkoxy, or Ci-C4heteroalkyl;
R3 is H or C C4alkyl;
n is 0, 1, or 2.
[00118] For any and all of the embodiments, substituents are selected from among from a subset of the listed alternatives. For example, in some embodiments, R1 is -C02RD or -C(=0)NHS02RE In some embodiments, R1 is -C02RD. In some embodiments, R1 is -C02H. In some embodiments, R1 is -C(=0)NHS02RE In some embodiments, RE is Ci-C6alkyl. In some embodiments, RE is -CH3 or - CH2CH3. In some embodiments, RE is -CH3. In some embodiments, RD is H, -CH3 or -CH2CH3. In some embodiments, RD is -CH2CH3. In some embodiments, RD is H.
[00119] In some embodiments, each Rc is independently halogen, -CN, -OH, -CH3, -CH2CH3, - CH(CH3)2, -CF3, -OCF3, -OCH3 or -OCH2CH3. In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.
[00120] In some embodiments,
Figure imgf000026_0001
is phenyl, 2-fluorophenyl, 2,3-difluorophenyl, 2,4- difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 2- bromophenyl, 3-bromophenyl, 2,4-dichlorophenyl, 2-hydroxyphenyl, 3 -hydroxyphenyl, 4- hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-trifluoromethylphenyl, 3- trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-fluoro-4-methoxyphenyl, 2-methylphenyl, 3- methylphenyl, 4-methylphenyl, 2-cyanophenyl, 3-cyanophenyl, or 4-cyanophenyl. In some
Figure imgf000026_0002
is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-trifluoromethylphenyl, or
Figure imgf000026_0003
2-methylphenyl. In some embodiments, is phenyl, 2-fluorophenyl, or 2-chlorophenyl.
Figure imgf000026_0004
In some embodiments, is phenyl. [00121] In some embodiments, R3 is -H, -CH3 or -CH2CH3. In some embodiments, R3 is -CH3 or - CH2CH3. In some embodiments, R3 is -CH3.
[00122] In some embodiments, R1 is -C02RD, or -C(=0)NHS02RE; RD is H or C C4alkyl; RE is C Qalkyl; R3 is -H, -CH3 or -CH2CH3.
[00123] In some embodiments, L3 is a substituted or unsubstituted C3-C4alkylene, a substituted or unsubstituted C3-C4fluoroalkylene, or a substituted or unsubstituted C3-C6heteroalkylene; where if L3 is substituted then L3 is substituted with 1, 2 or 3 R13; each R13 is independently F, -CH3, -CH2CH3, - CF3, or -OH.
[00124] In some embodiments, L3 is a substituted or unsubstituted butylene, a substituted or unsubstituted fiuorobutylene, or a substituted or unsubstituted difiuorobutylene; where if L3 is substituted then L3 is substituted with 1 or 2 R13.
[00125] In some embodiments, L3 is a substituted or unsubstituted C3-C6heteroalkylene; where if L3 is substituted then L3 is substituted with 1 or 2 R13.
[00126] In some embodiments, L3 is -(substituted or unsubstituted C3-C4alkylene)-0-, -(substituted or unsubstituted Ci-C3alkylene)-0-(substituted or unsubstituted Ci-C3alkylene)-, -0-(substituted or unsubstituted C3-C4alkylene)-, -(substituted or unsubstituted C3-C4alkylene)-S-, -(substituted or unsubstituted Ci-C3alkylene)-S-(substituted or unsubstituted Ci-C3alkylene)-, -S-(substituted or unsubstituted C3-C4alkylene)-, -(substituted or unsubstituted C3-C4alkylene)-NH-, -(substituted or unsubstituted Ci-C3alkylene)-NH-(substituted or unsubstituted Ci-C3alkylene)-, or -NH-(substituted or unsubstituted C3-C4alkylene)-.
[00127] In some embodiments, L3 is -NH-(substituted or unsubstituted C3-C4alkylene); where if L3 is substituted then L3 is substituted with R13.
[00128] In some embodiments, L3 is -(substituted or unsubstituted Ci-C3alkylene)-0-(substituted or unsubstituted Ci-C3alkylene)-, or -(substituted or unsubstituted Ci-C3alkylene)-S-(substituted or unsubstituted Ci-C3alkylene)-; where if L3 is substituted then L3 is substituted with R13.
[00129] In some embodiments, L3 is -(substituted or unsubstituted ethylene)-0-(substituted or unsubstituted methylene)-, or -(substituted or unsubstituted ethylene)-S-(substituted or unsubstituted methylene)-; where if L3 is substituted then L3 is substituted with R13.
[00130] In some embodiments, L3 is a substituted or unsubstituted C3-C4alkylene, a substituted or unsubstituted C3-C4fluoroalkylene, or a substituted or unsubstituted C3-C6heteroalkylene.
[00131] In some embodiments, L3 is a substituted or unsubstituted butylene, a substituted or unsubstituted fiuorobutylene, or a substituted or unsubstituted difiuorobutylene.
[00132] In some embodiments, L3 is a substituted or unsubstituted C3-C6heteroalkylene. In some embodiments, L3 is a substituted or unsubstituted C3-C4heteroalkylene.
[00133] In some embodiments, L3 is -NH-(substituted or unsubstituted C3-C4alkylene). [00134] In some embodiments, L3 is -(substituted or unsubstituted Ci-C3alkylene)-0-(substituted or unsubstituted Ci-C3alkylene)-, or -(substituted or unsubstituted Ci-C3alkylene)-S-(substituted or unsubstituted Ci-C3alkylene)-. In some embodiments, L3 is -(substituted or unsubstituted ethylene)- 0-(substituted or unsubstituted methylene)-, or -(substituted or unsubstituted ethylene)-S-(substituted or unsubstituted methylene)-.
[00135] In some embodiments, L3 is substituted with 1, 2 or 3 R13. In some embodiments, L3 is substituted with 1 or 2 R13. In some embodiments, L3 is substituted with R13. In some embodiments, L3 is unsubstituted. In some embodiments, if L3 is substituted then L3 is substituted with 1, 2 or 3 R13. In some embodiments, if L3 is substituted then L3 is substituted with 1 or 2 R13. In some
embodiments, if L3 is substituted then L3 is substituted with R13. In some embodiments, L3 is unsubstituted. In some embodiments, each R13 is independently F, Ci-C4alkyl, Ci-C4fiuoroaikyl, or - OH. In some embodiments, each R13 is independently F, Ci-C4alkyl, or -OH. In some embodiments, each R13 is independently Ci-C4alkyl, or -OH. In some embodiments, each R13 is independently F, - CH3, -CH2CH3, -CF3, or -OH. In some embodiments, each R13 is independently F, -CH3, or -OH. In some embodiments, each R13 is independently -CH3, or -OH. In some embodiments, R13 is F, -CH3, - CH2CH3, -CF3, or -OH. In some embodiments, R13 is F, -CH3, -CH2CH3, or -OH. In some embodiments, R13 is -CH3 or -OH. In some embodiments, R13 is Ci-C4alkyl, or -OH.
[00136] In some embodiments, the LPA receptor antagonist has the structure of Formula (VII) or a pharmaceutically acceptable salt thereof:
Figure imgf000028_0001
Formula (VII)
wherein,
-C02RD, -C(=0)NHS02RE, -C(=0)N(RD)2, -CN, or tetrazolyl;
RDis H or C C6 alkyl;
RE is C1-C6 alkyl or a substituted or unsubstituted phenyl;
L2 is absent, -C(=0)-, -N(RD)-, substituted or unsubstituted C1-C4 alkylene, or substituted or unsubstituted Ci-C4heteroalkylene, where if L2 is substituted, then L2 is substituted with R , where R is F, C C4alkyl, -OH, or -ORu;
ring A is a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic Ci-C5heteroarylene, where if ring A is substituted, then ring A is substituted with 1 or 2 R14, each R14 is independently selected from halogen, -CN, -OH, Ci-C4alkyl, C
C4fluoroalkyl, Ci-C4fluoroalkoxy, Ci-C4alkoxy, and Ci-C4heteroalkyl;
L4 is absent, or a substituted or unsubstituted C1-C4 alkylene, where if L4 is substituted then
L4 is substituted with R13, where R13 is F, C C4alkyl, -OH, or -ORD;
R3 is H or Ci-C4 alkyl;
each Rc is independently selected from halogen, -CN, -OH, Ci-C4alkyl, Ci-C4fluoroalkyl, C
C4fluoroalkoxy, Ci-C4alkoxy, and Ci-C4heteroalkyl;
n is 0, 1 or 2.
[00137] For any and all of the embodiments, substituents are selected from among from a subset of the listed alternatives. For example, in some embodiments, R1 is -C02RD or -C(=0)NHS02RE In some embodiments, R1 is -CO2R13. In some embodiments, R1 is -CO2H. In some embodiments, R1 is -C(=0)NHS02RE In some embodiments, RE is Ci-C6 alkyl. In some embodiments, RE is -CH3 or - CH2CH3. In some embodiments, RD is H, -CH3 or -CH2CH3. In some embodiments, RD is H.
[00138] In some embodiments, R3 is Ci-C4alkyl. In some embodiments, R3 is H, -CH3, or - CH2CH3. In some embodiments, R3 is -CH3, or -CH2CH3. In some embodiments, R3 is -CH3. In some embodiments, R3 is H.
[00139] In some embodiments, L2 is absent, -C(=0)-, -N(RD)-, substituted or unsubstituted C1-C4 alkylene, or substituted or unsubstituted Ci-C4heteroalkylene, where if L2 is substituted, then L2 is substituted with R12. In some embodiments, L2 is -N(RD)-, substituted or unsubstituted C1-C2 alkylene, or substituted or unsubstituted Ci-C2 heteroalkylene, where if L2 is substituted, then L2 is substituted with R12. In some embodiments, L2 is -N(H)-, -N(CH3)-, substituted or unsubstituted methylene, or substituted or unsubstituted ethylene, where if L2 is substituted, then L2 is substituted with R12. In some embodiments, L2 is -N(H)-. In some embodiments, L2 is substituted or
unsubstituted methylene, where if L2 is substituted, then L2 is substituted with R12.
[00140] In some embodiments, L2 is selected from a bond, Ci-C4alkylene, -C(=0)-, -CH(OH)-, -
CH(ORD)-, -CH2CH(OH)-, - CH2CH(ORD)-, -CH2S-, -CH2S(0)-, -CH2S(0)2-, -SCH2-, - S(0)CH2-, - S(0)2CH2-, -CH2O-, -OCH2-, -S(0)2CH2-, -N(H)-, -CH2N(H)-, or -N(H)CH2-.
[00141] In some embodiments, L2 is absent, -C(=0)-, -NH-, -N(CH3)-, -CH2-, -CH2CH2-, - CH(CH3)-, -CH2CH(CH3)-, -CH(CH3)CH2-, -CH(OH)-, -CH(ORD)-, -CH2CH(OH)-, -CH2CH(ORD)-, -CH(OH)CH2-, -CH(ORD)CH2-, -CH2NH-, -CH(CH3)NH-, -NHCH2- or -NHCH(CH3)-. In some embodiments, L2 is -NH-, -N(CH3)-, -CH2-, -CH(CH3)-, -CH(OH)-, -CH(ORD)-, -CH2NH-, - CH(CH3)NH-, -NHCH2- or -NHCH(CH3)-. In some embodiments, L2 is -NH-, -N(CH3)-, -CH2NH-, - CH(CH3)NH-, -NHCH2- or -NHCH(CH3)-. In some embodiments, L2 is -NH-. In some embodiments, L2 is -CH2-, -CH(CH3)-, -CH(OH)-, -CH(ORD)-, -CH2NH-, -CH(CH3)NH-, -NHCH2- or - NHCH(CH3)-. In some embodiments, L2 is -CH2-, -CH(CH3)-, -CH(OH)-, or -CH(ORD)-. In some embodiments, L2 is -CH2- or -CH(OH)-. In some embodiments, L2 is -CH(OH)-. In some embodiments, L2 is -CH2-.
[00142] In some embodiments, R12 is F, -CH3, -CH2CH3, -OH, -OCH3, or -OCH2CH3. In some embodiments, R12 is -CH3, or -OH.
[00143] In some embodiments, R1 is -C02RD, or -C(=0)NHS02RE; L2 is absent, -C(=0)-, -NH-, - N(CH3)-, -CH2-, -CH2CH2-, -CH(CH3)-, -CH2CH(CH3)-, -CH(CH3)CH2-, -CH(OH)-, -CH(ORD)-, - CH2CH(OH)-, -CH2CH(ORD)-, -CH(OH)CH2-, -CH(ORD)CH2-, -CH2NH-, -CH(CH3)NH-, -NHCH2- or -NHCH(CH3)-; L4 is absent, -CH2-, -CH(CH3)-, -CH(OH)-, -CH2CH2-, -CH2CH(CH3)-, - CH(CH3)CH2-, -CH2CH(OH)-, or -CH(OH)CH2-; R3 is -H, -CH3 or -CH2CH3.
[00144] In some embodiments, each Rc is halogen, -OH, -CH3, -CH2CH3, -CF3, -OCF3, -OCH3, - OCH2CH3, -CH2OCH3, -CH2OCH2CH3, or -CH2N( CH3)2. In some embodiments, each Rc is independently selected from halogen, -OH, -CH3, -CH2CH3, -CF3, -OCF3, -OCH3 and -OCH2CH3.
[00145] In some embodiments, ring A is a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic Ci-C5heteroarylene, where if ring A is substituted, then ring A is substituted with 1 or 2 R14.
[00146] In some embodiments, ring A is a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic Ci-Csheteroarylene containing 1-4 N atoms, 0 or 1 O atoms and 0 or 1 S atoms, where if ring A is substituted, then ring A is substituted with 1 or 2 R14.
[00147] In some embodiments, ring A is a substituted or unsubstituted monocyclic Cr
Csheteroarylene containing 1-4 N atoms, 0 or 1 O atoms and 0 or 1 S atoms, where if ring A is substituted, then ring A is substituted with 1 or 2 R14.
[00148] In some embodiments, ring A is a substituted or unsubstituted 5-membered monocyclic C C4heteroarylene containing 1-4 N atoms, 0 or 1 O atoms and 0 or 1 S atoms, where if ring A is substituted, then ring A is substituted with 1 or 2 R14.
[00149] In some embodiments, ring A is a substituted or unsubstituted 6-membered monocyclic C3- Csheteroarylene containing 1-3 N atoms, where if ring A is substituted, then ring A is substituted with 1 or 2 R14.
[00150] In some embodiments, ring A is a substituted or unsubstituted monocyclic ring wherein the groups -L2- and -L4- are in a 1 ,2-relationship on ring A (i.e. an ortho relationship). In some embodiments, ring A is a substituted or unsubstituted monocyclic ring wherein the groups -L2- and - L4- are in a 1,3 -relationship on ring A (i.e. a meta relationship). In some embodiments, ring A is a substituted or unsubstituted monocyclic ring wherein the groups -L2- and -L4- are in a 1 ,4- relationship on ring A (i.e. a para relationship).
[00151] In some embodiments, ring A is unsubstituted or monosubstituted with R14. In some embodiments, ring A is unsubstituted. In some embodiments, ring A is monosubstituted with R14. [00152] In some embodiments, L4 is absent, or a substituted or unsubstituted methylene, or substituted or unsubstituted ethylene, where if L4 is substituted, then L4 is substituted with R13. In some embodiments, L4 is absent. In some embodiments, L4 is a substituted or unsubstituted methylene, where if L4 is substituted, then L4 is substituted with R13. In some embodiments, L4 is a substituted or unsubstituted ethylene, where if L4 is substituted, then L4 is substituted with R13.
[00153] In some embodiments, R13 is F, -CH3, -CH2CH3, -OH, -OCH3, or -OCH2CH3. In some embodiments, R13 is -CH3.
[00154] In some embodiments, L4 is absent, -CH2-, or -CH(CH3)-.
[00155] In some embodiments, L2 is -NH-, -CH2-, -CH2CH2-, -CH(CH3)-, -CH2CH(CH3)-, - CH(CH3)CH2-, -CH(OH)-, -CH2CH(OH)-, -CH(OH)CH2-, -CH2NH-, -CH(CH3)NH-, -NHCH2- or - NHCH(CH3)-; ring A is a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic Ci-Csheteroarylene containing 1-4 N atoms, 0 or 1 O atoms and 0 or 1 S atoms, where if ring A is substituted, then ring A is substituted with 1 or 2 R14; L4 is absent, -CH2-, or -CH(CH3)-; R3 is -CH3.
[00156] In some embodiments, ring A is a substituted or unsubstituted phenyl, where if ring A is substituted, then ring A is substituted with 1 or 2 R14.
[00157] In some embodiments, ring A is a substituted or unsubstituted monocyclic C
Csheteroarylene containing 1-4 N atoms, 0 or 1 O atoms and 0 or 1 S atoms, where if ring A is substituted, then ring A is substituted with 1 or 2 R14.
[00158] In some embodiments, ring A is a substituted or unsubstituted 5-membered monocyclic C C4heteroarylene containing 1-4 N atoms, 0 or 1 O atoms and 0 or 1 S atoms, where if ring A is substituted, then ring A is substituted with 1 or 2 R14.
[00159] In some embodiments, ring A is a substituted or unsubstituted furanyl, a substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted oxadiazolyl, or substituted or unsubstituted thiadiazolyl, where if ring A is substituted, then ring A is substituted with 1 or 2 R14.
[00160] In some embodiments, each R14 is independently selected from halogen, -CN, -OH, -CH3, - CH2CH3, -CF3, -OCF3, -OCH3 and -OCH2CH3. In some embodiments, each R14 is halogen, -CN, - OH, -CH3, -CH2CH3, -CF3, -OCF3, -OCH3 or -OCH2CH3. In some embodiments, each R14 is independently selected from halogen, -OH, and -CH3. . In some embodiments, R14 is halogen, -OH, or -CH3. In some embodiments, each R14 is independently selected from halogen and -CH3.
Figure imgf000032_0001
[00162] In some embodiments, ring A is a substituted or unsubstituted 6-membered monocyclic C3- C5heteroarylene containing 1-3 N atoms, where if ring A is substituted, then ring A is substituted with l or 2 R14.
[00163] In some embodiments, ring A is a substituted or unsubstituted pyridinylene, a substituted or unsubstituted pyridazinylene, a substituted or unsubstituted pyrimidinylene, a substituted or unsubstituted pyrazinylene, or a substituted or unsubstituted triazinylene, where if ring A is substituted, then ring A is substituted with 1 or 2 R14.
[00164] In some embodiments, ring A is a substituted or unsubstituted pyridinylene, where if ring A is substituted, then ring A is substituted with 1 or 2 R14.
[00165] In some embodiments, ring A is *0* , f ,
Figure imgf000032_0002
, ;
Figure imgf000032_0003
Figure imgf000033_0001
[00166] In some embodiments, R1 is -C02RD, or -C(=0)NHS02RE; RD is H or C C4 alkyl; RE is Ci-C4 alkyl; L2 is -CH2-, -CH(CH3)-, or -CH(OH)-; ring A is a substituted or unsubstituted 5- membered monocyclic Ci-C4heteroarylene containing 1-4 N atoms, 0 or 1 O atoms and 0 or 1 S atoms, where if ring A is substituted, then ring A is substituted with R14; L4 is -CH2- or -CH(CH3)-; p is 0 or 1.
[00167] In some embodiments, R1 is -C02RD, or -C(=0)NHS02RE; RD is H or C C4 alkyl; RE is Ci-C4 alkyl; L2 is -CH2-, -CH(CH3)-, or -CH(OH)-; ring A is a substituted or unsubstituted 5- membered monocyclic Ci-C4heteroarylene containing 1-4 N atoms and 0 or 1 O atoms, where if ring A is substituted, then ring A is substituted with R14, R14 is halogen, -CN, -OH, -CH3, -CH2CH3, -CF3, -OCF3, -OCH3 or -OCH2CH3; L4 is -CH2- or -CH(CH3)-; n is 0 or 1.
[00168] In some embodiments, R1 is -C02RD, or -C(=0)NHS02RE; RD is H or C C4alkyl; RE is C C4alkyl; L2 is -NH-, -CH2-, -CH(CH3)-, -CH(OH)-, -NHCH2- or -NHCH(CH3)-; ring A is a substituted or unsubstituted 6-membered monocyclic C3-C5heteroarylene containing 1-3 N atoms, where if ring A is substituted, then ring A is substituted with R14; L4 is absent, -CH2-, or -CH(CH3)-; p is 0 or 1.
[00169] In some embodiments, R1 is -C02RD, or -C(=0)NHS02RE; RD is H or C C4alkyl; RE is C C4alkyl; L2 is -NH-, -CH2-, -CH(CH3)-, -CH(OH)-, -NHCH2- or -NHCH(CH3)-; ring A is a substituted or unsubstituted pyridinylene, where if ring A is substituted, then ring A is substituted with R14, R14 is halogen, -CN, -OH, -CH3, -CH2CH3, -CF3, -OCF3, -OCH3 or -OCH2CH3; L4 is absent, -CH2-, or -CH(CH3)-; n is 0 or 1.
[00170] In some embodiments, n is 0, 1 or 2. In some embodiments, n is 0 or 1. In some
embodiments, n is 0. In some embodiments, n is 1. [00171] In some embodiments, *-G (R c )n is phenyl, 2-fluorophenyl, 2,3-difluorophenyl, 2,4- difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 2- bromophenyl, 3-bromophenyl, 2,4-dichlorophenyl, 2-hydroxyphenyl, 3- hydroxyphenyl, 4- hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-trifluoromethylphenyl, 3- trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-fluoro-4-methoxyphenyl, 2-methylphenyl, 3- methylphenyl, 4-methylphenyl, 2-cyanophenyl, 3-cyanophenyl, or 4-cyanophenyl. [00172] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.
[00173] In some embodiments, the LPA receptor antagonist is selected from compounds (or a pharmaceutically acceptable salt, prodrug, active metabolite, or a pharmaceutically acceptable solvate thereof) described in U.S. Patent Nos. 6,964,975; 7,288,558 and U.S. Application Publication No. 2006/0194850, each of which is herein incorporated by reference.
[00174] In some embodiments, the LPA receptor antagonist is 3-[[[4-[4-[[[l-(2- chlorophenyl)ethoxy]carbonyl]amino]-3-methyl-5-isoxazolyl]phenyl]methyl]thio]-propanoic acid.
[00175] In some embodiments, the LPA receptor antagonists contemplated for use herein (including pharmaceutically acceptable salts, solvates, and prodrugs thereof) are antagonists of LPAI and optionally at least one of the LPA receptors selected from LPA2, LPA3, LPA4; LPA5 and LPA6. In one embodiment, the LPA receptor antagonists are antagonists LPAi and/or LP A3. In some embodiments, the LPA compounds are antagonists of LPAi and/or LPA2.
[00176] In one aspect, LPA receptor antagonists contemplated for use in any of the embodiments disclosed herein are selective LPAI receptor antagonists. "Selectivity" for one LPA receptor versus other LPA receptors means that the compound has an IC50 (Ca Flux assay) for the indicated LPA receptor that is at least 10-fold less than the IC50 for other LPA receptors. In some embodiments, selectivity for one LPA receptor versus other LPA receptor means that the compound has an IC50 for the indicated LPA receptor that is at least 10-fold, at least 20-fold, at least 40-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 500-fold, or at least 1000-fold, less than the IC50 for other LPA receptors. For example, a selective LPAi receptor antagonist has an IC50 that is at least 10-fold, at least 20-fold, at least 40-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 500-fold, or at least 1000-fold, less than the IC50 for other LPA receptors (e.g. LPA2, LPA3).
[00177] In some embodiments, pharmaceutically acceptable salts are obtained by reacting an LPA receptor antagonist compound with acids. Pharmaceutically acceptable salts are also obtained by reacting an LPA receptor antagonist compound with a base. In one aspect LPA receptor antagonists described herein are used as pharmaceutically acceptable salts. The type of pharmaceutical acceptable salts, include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable: inorganic acid to form a salt such as, for example, a hydrochloric acid salt, a hydrobromic acid salt, a sulfuric acid salt, a phosphoric acid salt, a metaphosphoric acid salt, and the like; or with an organic acid to form a salt, such as, for example, an acetic acid salt, a propionic acid salt, a hexanoic acid salt, a cyclopentanepropionic acid salt, a glycolic acid salt, a pyruvic acid salt, a lactic acid salt, a malonic acid salt, a succinic acid salt, a malic acid salt, a maleic acid salt, a fumaric acid salt, a trifiuoroacetic acid salt, a tartaric acid salt, a citric acid salt, a benzoic acid salt, a 3-(4-hydroxybenzoyl)benzoic acid salt, a cinnamic acid salt, a mandelic acid salt, a methanesulfonic acid salt, an ethanesulfonic acid salt, a 1 ,2-ethanedisulfonic acid salt, a 2-hydroxyethanesulfonic acid salt, a benzenesulfonic acid salt, a toluenesulfonic acid salt, a 2-naphthalenesulfonic acid salt, a 4-methylbicyclo-[2.2.2]oct-2-ene-l-carboxylic acid salt, a glucoheptonic acid salt, a 4,4'-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid) salt, a 3- phenylpropionic acid salt, a trimethylacetic acid salt, a tertiary butylacetic acid salt, a lauryl sulfuric acid salt, a gluconic acid salt, a glutamic acid salt, a hydroxynaphthoic acid salt, a salicylic acid salt, a stearic acid salt, a muconic acid salt, a butyric acid salt, a phenylacetic acid salt, a phenylbutyric acid salt, a valproic acid salt, and the like; (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion (e.g. a lithium salt, a sodium salt, potassium salt), an alkaline earth ion (e.g. a magnesium salt, or a calcium salt), or an aluminum ion (e.g. an aluminum salt). In some cases, LPA receptor antagonist compounds described herein are reacted with an organic base to form a salt, such as, but not limited to, an ethanolamine salt, a diethanolamine salt, a triethanolamine salt, a tromethamine salt, a N-methylglucamine salt, a dicyclohexylamine salt, a tris(hydroxymethyl)methylamine salt. In other cases, LPA receptor antagonist compounds described herein form salts with amino acids such as, but not limited to, an arginine salt, a lysine salt, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. In some embodiments, LPA receptor antagonist compounds are prepared and utilized as sodium salts.
[00178] In some embodiments, the LPA receptor antagonist compounds described herein possess one or more stereocenters and each center exists independently in either the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof.
[00179] In some embodiments, LPA antagonists presented herein are used as a single enantiomer. In some embodiments, LPA antagonists presented herein are used as a single enantiomer that is optically pure (i.e. substantially free of the other isomer). In some embodiments, LPA antagonists presented herein are used as a single enantiomer of any optical purity. In some embodiments, LPA antagonists presented herein are used as a racemic mixture.
Certain Terminology
[00180] An "alkyl" group refers to an aliphatic hydrocarbon group. The alkyl group may be a saturated alkyl group or an unsaturated alkyl group. The alkyl moiety, whether saturated or unsaturated, may be branched or straight chain. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, hexyl, allyl, but-2-enyl, but-3-enyl, and the like. In one aspect the alkyl is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. [00181] The term "alkylene" refers to a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, - CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like.
[00182] An "alkoxy" group refers to a (alkyl)O- group, where alkyl is as defined herein.
[00183] "Aryl" refers to phenyl or naphthalenyl. In one aspect, an aryl is a phenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). Examplary arylenes include, but are not limited to, phenyl- 1,2-ene, phenyl- 1, 3 -ene, and phenyl- 1,4-ene.
[00184] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. Cycloalkyls may be saturated, or partially unsaturated. In some embodiments, cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Depending on the structure, a cycloalkyl group can be a monoradical or a diradical (i.e., an cycloalkylene group, such as, but not limited to, cyclopropan-l,l-diyl, cyclobutan-l,l-diyl, cyclopentan- 1 , 1 -diyl, cyclohexan- 1 , 1 -diyl, cyclohexan- 1 ,4-diyl, cycloheptan- 1 , 1 -diyl, and the like).
[00185] The term "halo" or, alternatively, "halogen" or "halide" means fluoro, chloro, bromo or iodo.
[00186] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by one or more halide atoms.
[00187] The term "haloalkyl ene" refers to an alkylene group in which one or more hydrogen atoms are replaced by one or more halide atoms.
[00188] The term "fluoroalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom.
[00189] The term "fluoroalkylene" refers to an alkylene in which one or more hydrogen atoms are replaced by a fluorine atom.
[00190] The term "heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g. , oxygen, nitrogen (e.g. NH or Nalkyl), sulfur, or combinations thereof.
[00191] The term "heteroalkylene" refers to an alkylene group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, or combinations thereof. Examplary heteroalkylenes include, but are not limited to, -OCH2-, - OCH(CH3)-, -OC(CH3)2-, -OCH2CH2-, -CH20-, -CH(CH3)0-, -C(CH3)20-, -CH2CH20-, -CH2OCH2- , -CH2OCH2CH2-, -CH2CH2OCH2-, -SCH2-, -SCH(CH3)-, -SC(CH3)2-, -SCH2CH2-, -CH2S-, - CH(CH3)S-, -C(CH3)2S-, -CH2CH2S-, -CH2SCH2-, -CH2SCH2CH2-, -CH2CH2SCH2-, -S02CH2-, - S02CH(CH3)-, -S02C(CH3)2-, -S02CH2CH2-, -CH2S02-, -CH(CH3)S02-, -C(CH3)2S02-, -
CH2CH2S02-, -CH2S02CH2-, -CH2S02CH2CH2-, -CH2CH2S02CH2-, -NHCH2-, -NHCH(CH3)-, - NHC(CH3)2-, -NHCH2CH2-, -CH2NH-, -CH(CH3)NH-, -C(CH3)2NH-, -CH2CH2NH-, -CH2NHCH2-, - CH2NHCH2CH2-, -CH2CH2NHCH2-, and the like.
[00192] The term "heteroaryl" refers to an aromatic ring that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. In one aspect, a heteroaryl contains 0-3 N atoms. In another aspect, a heteroaryl contains 1-3 N atoms. In another aspect, a heteroaryl contains 0-3 N atoms, 0-1 O atoms, and 0-1 S atoms. In another aspect, a heteroaryl is a monocyclic or bicyclic heteroaryl. In one aspect, heteroaryl is a Ci-Cgheteroaryl. In one aspect, monocyclic heteroaryl is a Ci-Csheteroaryl. In one aspect, monocyclic heteroaryl is a 5- membered or 6-membered heteroaryl. In one aspect, bicyclic heteroaryl is a C6-C9heteroaryl.
Depending on the structure, a heteroaryl group can be a monoradical or a diradical (i.e., a
heteroarylene group).
[00193] A "heterocycloalkyl" refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, the heterocycloalkyl is selected from oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and indolinyl. The term heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. In one aspect, a heterocycloalkyl is a C2-Cioheterocycloalkyl. In another aspect, a heterocycloalkyl is a C4-Cioheterocycloalkyl. In one aspect, a heterocycloalkyl contains 0-2 N atoms. In another aspect, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms or 0-1 S atoms.
[00194] The term "membered ring" is meant to denote the number of skeletal atoms that constitute the ring. Thus, for example, cyclohexyl, pyridinyl, pyranyl and thiopyranyl are 6-membered rings and cyclopentyl, pyrrolyl, furanyl, and thienyl are 5-membered rings.
[00195] The term "moiety" refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
[00196] The term "optionally substituted" or "substituted" means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -C02H, -C02alkyl, -C(=0)NH2, -C(=0)NHalkyl, - C(=0)N(alkyl)2, -S(=0)2NH2, -S(=0)2NH(alkyl), -S(=0)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, -S-alkyl, or -S(=0)2alkyl. In some embodiments, an optional substituent is selected from halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, - OCH3, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, substituted groups are substituted with one of the preceding groups. [00197] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof can be chosen by one skilled in the field to provide stable moieties and compounds.
[00198] In certain embodiments, the compounds presented herein possess one or more stereocenters and each center independently exists in either the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns.
[00199] The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds having the structure of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI) or Formula (VII), as well as active metabolites of these compounds having the same type of activity. In some situations, compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In specific embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In other embodiments, the compounds described herein exist in unsolvated form.
[00200] The term "modulate," as used herein, means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.
[00201] The term "antagonist," as used herein, refers to a molecule such as a compound, which diminishes, inhibits, or prevents the action of another molecule or the activity of a receptor site.
Antagonists include, but are not limited to, competitive antagonists, non-competitive antagonists, uncompetitive antagonists, partial agonists and inverse agonists.
[00202] The term "LPA-dependent", as used herein, refers to conditions or disorders that would not occur, or would not occur to the same extent, in the absence of LPA.
[00203] The term "LPA-mediated", as used herein, refers to refers to conditions or disorders that might occur in the absence of LPA but can occur in the presence of LPA.
[00204] The terms "effective amount" or "therapeutically effective amount," as used herein, refer to a sufficient amount of an agent or a compound (e.g. an LPA receptor antagonist described herein) being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of an LPA receptor antagonist in an inhalable formulation described herein that is required to provide a clinically significant decrease in disease symptoms. An appropriate "effective" amount in any individual case may be determined using techniques, such as a dose escalation study.
[00205] The term "subject" or "individual" or "patient" encompasses mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one embodiment, the mammal is a human.
[00206] The terms "treat," "treating" or "treatment," as used herein, include alleviating, abating or ameliorating at least one symptom of a disease disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
[00207] The terms "prevent," "preventing," or "prevention" and other grammatical equivalents used herein include inhibiting (arresting or stopping) the development of a disorder and/or inhibiting (arresting or stopping) the further progression of a disorder. These terms are meant to include prophylaxis. For prophylactic benefit, the compositions are administered to an individual suspected of having a particular disorder, at risk of developing a disorder or to an individual reporting one or more symptoms of a disorder or at risk of reocurrence of a disease.
Inhalable formulations
[00208] Inhalable formulations described herein deliver LPA receptor antagonists to the respiratory tree of a mammal. In certain instances, localized pulmonary administration of an LPA receptor antagonist reduces or eliminates side-effects associated with systemic administration of LPA receptor antagonists. The formulations described herein are administered by a nasal or oral respiratory route and are suitable for delivery of LPA receptor antagonists to the lungs of a mammal. Inhalable formulations described herein include but are not limited to solutions, suspensions, colloidal dispersions, emulsions, sprays, dry powders, aerosols or drops.
Solutions
[00209] Described herein are inhalable formulations that include an LPA receptor antagonist wherein the inhalable formulation is in the form of a solution. In certain instances, pulmonary delivery of an LPA receptor antagonist is achieved by administration of an inhalable solution formulation by the nasal respiratory route of a mammal. In certain instances, the solution is administered by an oral respiratory route to the lungs of a mammal.
[00210] In certain instances, the solution comprises an LPA receptor antagonist or a salt thereof dissolved in sterile water and/or 0.9% sodium chloride solution. Small quantities of an alcohol or glycerin are used to solubilize the LPA receptor antagonist compound. In some instances, the solutions comprise a pH modifying agent to solubilize the LPA receptor antagonist. In certain instances, a pH-modifying agent maintains a solution pH of 5.5-7.5 and solubilizes the LPA receptor antagonist (e.g., an acid salt of an LPA receptor antagonist). In certain instances, the solution further comprises a preservative and/or a stabilizer. In certain instances, sterile solutions are obtained in the absence of a preservative and/or a stabilizer using filtration systems (e.g., 0.2 μ filtration systems) and/or heat treatment. In certain embodiments, the solution comprises a surfactant to enhance solubility of an LPA receptor antagonist. In certain embodiments, the surfactant concentration is kept as low as possible to minimize foaming that might interfere with proper administration. In certain embodiments, the inhalable solution formulation is isotonic with physiological fluids (e.g., osmolality of about 290 mOsm). In some instances, the inhalable solution formulation is hypotonic with physiological fluids. In some instances the osmolarity of an inhalable formulation is from about 250 to about 450 mOsm/L. In some instances the osmolarityof an inhalable formulation described herein is about 250-300 mOsm/L, about 260-310 mOsm/L, about 270-320 mOsm/L, about 280-330 mOsm/L, about 290-340 mOsm/L, about 300-350 mOsm/L, about 310-360 mOsm/L, or about 320- 370 mOsm/L.
Suspensions, emulsions and colloidal dispersions
[00211] Described herein, in certain embodiments, is an inhalable formulation comprising an LPA- receptor antagonist wherein the inhalable formulation is in the form of an emulsion, a colloidal dispersion or a suspension. The inhalable formulation that is in the form of an emulsion, a colloidal dispersion or a suspension is suitable for pulmonary delivery of LPA receptor antagonists in a mammal. The inhalable formulation that is in the form of an emulsion, a colloidal dispersion or a suspension is administered by the nasal or oral respiratory route in a mammal. In some instances, suspensions, emulsions or colloidal dispersions comprise a propellant system (e.g., liquified gas) with or without a cosolvent. The fomulations further comprise pH-modifying agents, preservatives and/or stabilizers. In certain instances, sterile formulations are obtained in the absence of a preservative and/or a stabilizer using filtration systems (e.g., 0.2 μ filtration systems) and/or heat treatment. In certain embodiments, the suspensions, emulsions or colloidal dispersions comprise a surfactant to enhance solubility of an LPA receptor antagonist. In certain embodiments, the surfactant
concentration is kept as low as possible to minimize foaming that might interfere with proper administration. In certain instances, the liquid phase (e.g., a cosolvent) of a suspension, emulsion or colloidal dispersion has a density similar to the density of the suspensoid. In certain instances, the liquid phase is a cosolvent that partially dissolves or does not dissolve the LPA receptor antagonist, thus minimizing particle size growth resulting from the dissolved compound crystallizing out onto crystals present in the suspenoid. In certain embodiments, an inhalable formulation described herein is isotonic with physiological fluids (e.g., osmolality of about 290 mOsm). In some instance an inhalable formulation described herein is hypotonic with physiological fluids. In certain instances, the suspensions, emulsions or colloidal dispersions comprise tonicity agents (e.g., sodium chloride, potassium chloride or the like) that render the formulation hypotonic. In certain instances, hypotonic formulations allow for absorption of the LPA receptor antagonist from the pulmonary space into the alveoli. In some embodiments the suspensions, emulsions or colloidal dispersions are aqueous suspensions, emulsions or colloidal dispersions.
Dry Powders
[00212] Described herein, in certain embodiments, is an inhalable formulation comprising an LPA receptor antagonist wherein the inhalable formulation is in the form of a dry powder. The dry powder inhalable formulation is suitable for administration of an LPA receptor antagonist to the lungs of a mammal. The dry powder inhalable formulation is administered by the nasal or oral respiratory route in a mammal. In some instances the dry powder is fluidized when a mammal inhales. In some embodiments, dry powders are free of propellants. In some instances, dry powders are one-phase solid-particle blends. When actuated, in some instances, dry powders are two-phase gas-solid systems wherein the dry powder is dispersed in air.
[00213] Dry powders comprise micronized and/or nano-sized LPA receptor antagonist particles blended with larger carrier particles that prevent aggregation. The excipients and/or carriers in dry powders are endogenous to the lung and are easily metabolized or cleared. In some instances, dry powders contain lactose as a carrier. In some instances, dry powders comprise starch, mannitol or glucose as a carrier. In some instances, LPA receptor antagonist dry powders are formulated as liposomes comprising phospholipids (e.g., phosphatidylcholine), cholesterol, or the like. A carrier particle has low hygroscopicity (e.g., lactose) to prevent aggregation or caking due to absorption of moisture.
[00214] In some instances, a dry powder inhalable formulation described herein comprises nano- particles of an LPA receptor antagonist. In some instances dry powder inhalable formulations described herein comprise crystalline particles. In some embodiments, dry powder inhalable formulations described herein comprise amorphous particles.
Pulmonary absorption
[00215] The pulmonary absorption characteristics of dry powders, suspensions, emulsions and colloidal dispersions are determined by the particle size of the active ingredient (e.g., an LPA receptor antagonist described herein) in the formulation. Particles greater than 60 μηι in diameter are deposited in the trachea; particles between 20 - 60 μηι in diameter are deposited between the trachea and the bronchioles. Particles between 5-20 μηι in diameter are deposited in bronchioles. Particles less than 1 μηι in diameter remian airborne and are exhaled. In some instances, the particle size of an LPA receptor antagonist in an inhalable formulation described herein is 5 -20 μηι in diameter. [00216] In some instances, aerodynamic diameter of a particle is an appropriate measure of pulmonay absorption characteristics of particles in inhalable formulations described herein because it relates to particle dynamic behaviour. Particles larger than 5 μηι aerodynamic diameter deposit in the oral cavity or the pharynx and are cleared. Particles smaller than 1 μηι aerodynamic diameter are not deposited and are exhaled. In some instances, the aerodynamic diameter of an LPA receptor antagonist in an inhalable formulation described herein is 1 -5 μηι.
[00217] In some instances, any inhalable formulation described herein is a multimodal particulate formulation. A multimodal particulate formulation, by way of example, comprises a first population of particles (e.g., LPA receptor antagonist particles) have a first effective mean particle diameter and a second population of particles having a second mean particle diameter wherein the first effective mean particle diameter is at least 1.5 to 3 times the second effective mean particle diameter.
[00218] Ingredients in inhalable formulations described herein are processed to create particles in the respirable size range. Particle size reduction techniques include, by way of example, milling (e.g., air-attrition milling (jet milling), ball milling), spray drying and/or supercritical fluid crystallization.
[00219] Any inhalable formulation described herein is prepared using a suitable particle size detection technique. In some instances, LPA receptor antagonist particles and/or excipients and/or carriers are sized using cascade impactors. Cascade impactors contain orifices of deceasing size stacked on top of each other. Aerosolized particles are drawn through the impactor and deposit in different stages based on their inertia. Electrical low pressure impactors are a modification of a cascade impactor. The particles are charged before traversing the cascade of stages. The impact of the particles on stages produces an electrical current that is converted into particle-size data.
[00220] Alternatively, light scattering and/or laser diffraction techniques are used to calculate particle sizes. Different size particles diffract light at different angles and a computer algorithm interprets the diffraction data and calculates a particle size distribution. In some instances, imaging techniques are used to determine particle size. Digital images of particles are converted to binary data and a particle size data is derived using 2 or 3-dimensional representations of the particles.
Administration of inhalable formulations
[00221] In some instances, the inhalable formulations described herein are administered via an atomizer. An atomizer allows a stream of air to move at a high velocity over the tip of a tube dipped in a solution. The pressure at the tip of the tube is lowered and the solution is drawn into the air flow. The solution disperses into a fine spray or droplets that are carried into the inhaled stream of air. In some instances, the inhalable solution formulations described herein are administered with a nebulizer that is placed in the mouth. The spray, mist or fine droplets produced by atomizers or nebulizers allow the LPA receptor antagonist to reach the bronchioles in the lungs. In some embodiments, the inhalable formulations described herein comprise a propellant and are pressure packaged for administration of LP A receptor antagonist(s) using pressurized aerosols. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. In some instances, the inhalable formulations described herein are administered with a metered dose spray bottle that delivers a specific volume of a solution, suspension, emulsion or colloidal dispersion for inhalation. In some instances, the dry powder inhalable formulations described herein are administered with an insufflator. An insufflator consists of a rubber bulb connected to a container and a delivery pipe. As the bulb is squeezed, air is blown into the container and causes the powder to move. The particles are carried out via the delivery tube and are inhaled. In some intances the dry powder inhalable formulations described herein are administered with a puffer. The dry powder is placed in the puffer and the puffer is squeezed. A portion of the powder is ejected from the spout into the air and is inhaled. Capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator may be formulated containing a dry powder formulation described herein.
Excipients
[00222] Described herein, in certain embodiments, is an inhalable formulation for delivery to the lungs of a mammal that comprises one or more pH adjusting agents. pH adjusting agents or buffering agents, include, but are not limited to acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.
[00223] Described herein, in certain embodiments, is an inhalable formulation for delivery to the lungs of a mammal that comprises one or more tonicity agents. Tonicity agents are used to adjust the composition of the formulation to the desired isotonic range. Tonicity agents include one or more salts in an amount required to bring osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate. Other exemplary tonicity agents include mannitol, dextrose,
[00224] Described herein, in certain embodiments, is an inhalable formulation for delivery to the lungs of a mammal that comprises one or more preservatives to inhibit microbial activity. Suitable preservatives include benzoic acid, boric acid, p-hydroxybenzoates, alcohols, mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride. In certain embodiments, the formulations described herein optionally include one or more stabilizers (e.g., antioxidants) to enhance chemical stability where required. Suitable antioxidants include, by way of example only, ascorbic acid, methionine, sodium thiosulfate and sodium metabisulfite. In one embodiment, antioxidants are selected from metal chelating agents, thiol containing compounds and other general stabilizing agents.
[00225] Described herein, in certain embodiments, is an inhalable formulation for delivery to the lungs of a mammal that comprises one or more propellants. Exemplary propellants include one or mixture of chlorofluorocarbons, such as dichlorodifiuoromethane, trichlorofiuoromethane, dichlorotetrafluoroethane or the like, as well as hydrofluorocarbons, such as 1 , 1 , 1 ,2-tetrafluoroethane (HFC- 134a) and 1,1,1,2,3,3,3 -heptafluoropropane (HFC-227) or the like, carbon dioxide or other suitable gas. In certain embodiments, the propellants are used with a cosolvent. Exemplary cosolvents include alcohols such as ethyl alcohol, isopropyl alcohol, propylene glycol, hydrocarbons such as propane, butane, isobutane, pentane, isopentane, neopentane, and other propellants such as those commonly referred to as Propellants 11, 12, 114, 113, 142b, 152a 124, and dimethyl ether.
[00226] Described herein, in certain embodiments, is an inhalable formulation for delivery to the lungs of a mammal that comprises one or more surfactants. "Surfactants" are wetting agents that lower the surface tension of a liquid. Examples of surfactants for inhalable formulations include and are not limited to oils derived from natural sources, such as, corn oil, olive oil, cotton seed oil and sunflower seed oil; sorbitan esters, such as Sorbitan trioleate available under the trade name Span 85, Sorbitan mono-oleate available under the trade name Span 80, Sorbitan monolaurate available under the trade name Span 20, Polyoxyethylene (20) sorbitan monolaurate available under the trade name Tween 20, Polyoxyethylene (20) sorbitan mono-oleate available under the trade name Tween 80; lecithins derived from natural sources such as those available under the trade name Epikuron particularly Epikuron 200. Oleyl polyoxyethylene (2) ether available under the trade name Brij 92, Stearyl polyoxyethylene (2) available under the trade name Brij 72, Lauryl polyoxyethylene (4) ether available under the trade name Brij 30, Oleyl polyoxyethylene (2) ether available under the trade name Genapol 0-020, Block copolymers of oxyethylene and oxypropylene available under the trade name Synperonic, Oleic acid, Synthetic lecithin, Diethylene glycol dioleate, Tetrahydrofurfuryl oleate, Ethyl oleate, Isopropyl myristate, Glyceryl trioleate, Glyceryl monolaurate, Glyceryl mono- oleate, Glyceryl monostearate, Glyceryl monoricinoleate, Cetyl alcohol, Stearyl alcohol,
Polyethylene glycol 400, and Cetyl pyridinium chloride.
[00227] In one embodiment, the aqueous suspensions, emulsions and colloidal dispersions described herein remain in a homogenous state, as defined in The USP Pharmacists' Pharmacopeia (2005 edition, chapter 905), for at least 4 hours. In one embodiment, an aqueous suspension is re-suspended into a homogenous suspension by physical agitation lasting less than 1 minute (e.g., by shaking a metered spray dispenser). In still another embodiment, no agitation is necessary to maintain a homogeneous aqueous dispersion. [00228] In some embodiments, the solution, emulsion, suspension and/or colloidal dispersion formulations also include inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and/or emulsifiers. Exemplary emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, sodium lauryl sulfate, sodium doccusate, cholesterol, cholesterol esters, taurocholic acid, phosphotidylcholine, oils, such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan, or mixtures of these substances, and the like.
[00229] In some embodiments, the inhalable formulations described herein are stable (e.g., with respect to pH, active ingredient) over a period of any of at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, at least about 8 weeks, at least about 4 months, at least about 5 months, at least about 6 months, or greater than 6 months.
[00230] In certain embodiments, the inhalable formulations described herein are designed for minimal pulmonary toxicity, irritation and/or allergic challenge to pulmonary tissues and include, for example, low amounts of excipients such as surfactants, preservatives and/or cosolvents.
Dosing
[00231] Disclosed herein, in certain embodiments, is an inhalable formulation of an LPA receptor antagonist compound wherein the inhalable formulation is administered for prophylactic and/or therapeutic treatments. In certain instances, amounts effective for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the mammal's health status and response to the drugs, and the judgment of the treating physician. In some embodiments, the dose of an LPA receptor antagonist is about 0.001% by weight to about 10% by weight of the inhalable formulation. In some embodiments, the dose of an LPA receptor antagonist is about 0.001%) by weight to about 5%> by weight of the inhalable formulation.
[00232] In some embodiments, where an LPA-dependent or LPA-mediated disease or condition does not improve, an inhalable formulation disclosed herein is administered chronically (i.e., for an extended period of time, including throughout the duration of the mammal's life). In some embodiments, where an LPA-dependent or LPA-mediated disease or condition does improve, an inhalable formulation disclosed herein is given continuously; alternatively, the dose of active agent being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday"). In some embodiments, a drug holiday lasts between 2 days and 1 year, including all integers in between. In some embodiments, the dose reduction during a drug holiday is from about 10%) to about 100%), including all integers in between.
[00233] In some embodiments, where an LPA-dependent or LPA-mediated disease or condition does improve, an inhalable formulation disclosed herein is administered as a maintenance dose. In some embodiments, where an LPA-dependent or LPA-mediated disease or condition does improve, an inhalable formulation disclosed herein is administered with reduced frequency or at a reduced dose.
[00234] In some embodiments, where an individual is suspected of having an LPA-dependent or LPA-mediated disease or condition, an inhalable formulation disclosed herein is administered as a prophylactic dose prior to onset of disease symptoms. In some embodiments, a prophylactic dose is a reduced dose compared to a therapeutic dose.
[00235] In some embodiments, the inhalable formulations described herein are generally administered in volumes of 25-250 μΐ^ per metered dose. In some instances, the inhalable formulations described herein are administered in volumes of less than 250 μί, less than 150 μί, less than 100 μί, or less than 50 μL·.
[00236] In any of the aforementioned embodiments, are further embodiments comprising single administrations of the effective amount of the LPA receptor antagonist, including further
embodiments in which (i) the LPA receptor antagonist is administered once a day; or (ii) the LPA receptor antagonist is administered to the mammal multiple times over the span of one day.
[00237] In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the LPA receptor antagonist, including further
embodiments in which (i) the compound is administered intermittently; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.
Patient Selection
[00238] In any of the aforementioned aspects involving the prevention or treatment of LPA- mediated diseases or conditions of the eye are further embodiments comprising identifying patients by screening for LPA receptor gene SNPs. Patients can be further selected based on increased LPA receptor expression in the tissue of interest. LPA receptor expression are determined by methods including, but not limited to, northern blotting, western blotting, quantitative PCR (qPCR), flow cytometry, autoradiography (using a small molecule radioligand or PET ligand). In some
embodiments, patients are selected based on the concentration of serum or tissue LPA measured by mass spectrometry. In some embodiments, patients are selected based on a combination of the above markers (increased LPA concentrations and increased LPA receptor expression). Combination Therapy
[00239] In certain instances, it is appropriate to administer at least one LPA receptor antagonist in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient upon receiving one of the compounds herein is inflammation, then it may be appropriate to administer an anti-inflammatory agent in combination with the initial therapeutic agent. Or in another example, a patient is presented with a situation in which antagonism of LPA receptors provides potential harm, for example, if the patient is wounded, antagonism of LPA receptors may lead to a delay in wound healing. In such an event, in certain embodiments, the patient benefits by administration of a local wound-healing agent (at the site of the wound) in combination with the co-existing administration of a LPA receptor antagonist.
[00240] Or, in one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant {i.e., by itself the adjuvant may have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, in some embodiments, the benefit experienced by a patient is increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
[00241] In one specific embodiment, a LPA receptor antagonist is co-administered with a second therapeutic agent, wherein the LPA receptor antagonist and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.
[00242] In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit.
[00243] In certain embodiments, different therapeutically-effective dosages of the compounds disclosed herein will be utilized in formulating pharmaceutical composition and/or in treatment regimens when the compounds disclosed herein are administered in combination with one or more additional agent, such as an additional therapeutically effective drug, an adjuvant or the like.
Therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens can be determined by means similar to those set forth hereinabove for the actives themselves. Furthermore, the methods of prevention/treatment described herein encompasses the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects. In some embodiments, a combination treatment regimen encompasses treatment regimens in which administration of a LPA receptor antagonist is initiated prior to, during, or after treatment with a second agent described herein, and continues until any time during treatment with the second agent or after termination of treatment with the second agent. It also includes treatments in which a LPA receptor antagonist and the second agent being used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period.
Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.
[00244] Compositions and methods for combination therapy are provided herein. In accordance with one aspect, the pharmaceutical compositions disclosed herein are used to treat LPA-dependent or LPA-mediated conditions.
[00245] It is understood that the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought, is modified in accordance with a variety of factors. These factors include the disease, disorder or condition from which the subject suffers, as well as the age, weight, sex, diet, and medical condition of the subject. Thus, in some instances, the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.
[00246] For combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated and so forth. In additional embodiments, when co-administered with one or more other therapeutic agents, the compound provided herein is administered either simultaneously with the one or more other therapeutic agents, or sequentially.
[00247] In combination therapies, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms. In one embodiment, one of the therapeutic agents is given in multiple doses, and in another, two (or more if present) are given as multiple doses. In some embodiments of non-simultaneous administration, the timing between the multiple doses vary from more than zero weeks to less than four weeks. In addition, the combination methods, compositions and formulations are not to be limited to the use of only two agents; the use of multiple therapeutic combinations is also envisioned.
[00248] The LPA receptor antagonist and combination therapies are administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies. Thus, in one embodiment, the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms. In specific embodiments, a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease. In some embodiments, the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject. For example, in specific embodiments, a compound described herein or a formulation containing the compound is administered for at least 2 weeks, about 1 month to about 5 years.
[00249] By way of example, therapies which combine a LPA receptor antagonist with inhibitors of LPA synthesis or LPA receptor antagonists, either acting at the same or other points in the LPA synthesis or signalling pathway, are encompassed herein for treating LPA-dependent or LPA- mediated diseases or conditions.
[00250] In one aspect, pharmaceutical compositions and methods disclosed herein include an additional therapeutic agent. In one aspect, the additional therapeutic agent is a therapeutic agent other than a LPA antagonist.
[00251] In one aspect, the pharmaceutical compositions disclosed herein that include a LPA receptor antagonist are co-administered with one or more additional therapeutically active agents selected from: corticosteroids, immunosuppresants, analgesics, anti-cancer agent, antiinflammatories, chemokine receptor antagonists, bronchodilators, leukotriene receptor antagonists, leukotriene formation inhibitors, monoacylglycerol kinase inhibitors, phospholipase Ai inhibitors, phospholipase A2 inhibitors, and lysophospho lipase D (lysoPLD) inhibitors, autotaxin inhibitors, decongestants, antihistamines, mucolytics, anticholinergics, antitussives, expectorants, and β-2 agonists.
[00252] In one aspect, the pharmaceutical compositions disclosed herein that include a LPA receptor antagonist are co-administered with (either separately or in the same formulation) an antibiotic. Antibiotics include, but are not limited to, polymyxin B sulfate / bacitracin zinc, polymyxin B / neomycin / gramicidin, polymyxin B/trimethoprim, polymyxin B/bacitracin, fluoroquinolones (e.g., ciprofloxacin, moxifloxacin, ofloxacin, gatifloxacin, levofloxacin), aminoglycosides (e.g. tobramycin, azithromycin, gentamicin, erythromycin, bacitracin.
[00253] In one aspect, the pharmaceutical compositions disclosed herein that include a LPA receptor antagonist are co-administered with (either separately or in the same formulation) a leukotriene modulator. Leukotriene modulators include, but are not limited to, 5-lipoxygenase inhibitors (5-LO) inhibitiors, 5-lipoxygenase activating protein (FLAP) inhibitor compounds, LTA4 hydrolase inhibitors, leukotriene receptor antagonist (e.g. CysLTi receptor antagonists, BLTiR antagonists).
[00254] In some embodiments, the LPA receptor antagonist is co-administered with (either separately or in the same formulation) an antiviral agent. Antiviral agents include, but are not limited to, acyclovir, vidarabine, trifluridine.
[00255] In some embodiments, the LPA receptor antagonist is co-administered with (either separately or in the same formulation) cyclosporine.
[00256] In some embodiments, the LPA receptor antagonist is co-administered with (either separately or in the same formulation) a leukotriene modulator. Leukotriene modulators include, but are not limited to 5-lipoxygenase (5-LO) inhibitors inhibitors, 5-lipoxygenase activating protein (FLAP) inhibitor compounds and leukotriene receptor antagonist (e.g. CysLTi receptor antagonists).
[00257] In some embodiments, a LPA receptor antagonist is used to treat or reduce fibrosis in a mammal. In some embodiments, a LPA antagonist is administered in combination with one or more immunosuppresants. Immunosuppressive therapy is clinically used to treat or prevent the rejection of transplanted organs and tissues; treatment of autoimmune diseases or diseases that are most likely of autoimmune origin; treatment of some other non-autoimmune inflammatory diseases, and in the treatment of fibrotic conditions.
[00258] In some embodiments, a LPA receptor antagonist is adminsitered with corticosteroids. In some embodiments, a LPA antagonist is adminsitered with an a therapeutic agent selected from among: Calcineurin inhibitors (such as, but not limited to, cyclosporin, tacrolimus); mTOR inhibitors (such as, but not limited to, sirolimus, everolimus); anti-proliferatives (such as, but not limited to, azathioprine, mycophenolic acid); corticosteroids (such as, but not limited to, prednisone, cortisone acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone, hydrocortisone); antibodies (such as, but not limited to, monoclonal anti-IL-2Ra receptor antibodies (basiliximab, daclizumab), polyclonal anti-T-cell antibodies (anti-thymocyte globulin (ATG), anti-lymphocyte globulin (ALG)), B-cell antagonists, rituximab, natalizumab.
[00259] Other therapeutic agents include, but are not limited to: cyclophosphamide, penicillamine, cyclosporine, nitrosoureas, cisplatin, carboplatin, oxaliplatin, methotrexate, azathioprine, mercaptopurine, pyrimidine analogues, protein synthesis inhibitors, dactinomycin, anthracyclines, mitomycin C, bleomycin, mithramycin, Atgam^, Thymoglobuline®, OKT3®, basiliximab, daclizumab, cyclosporin, tacrolimus, sirolimus, Interferons (IFN-β, IFN-γ), opioids, TNF binding proteins (infliximab, etanercept, adalimumab, golimumab), leflunomide, gold thioglucose, gold thiomalate, aurofin, sulfasalazine, hydroxychloroquinine, minocycline, rapamicin, mycophenolic acid, mycophenolate mofetil, FTY720, as well as those listed in US 7,060,697.
[00260] In one embodiment, a LPA antagonist is administered in combination with Cyclosporin A (CsA) or tacrolimus (FK506). In one embodiment, a LPA antagonist is administered to a mammal in combination with an anti-inflammatory agent including, but not limited to, non-steroidal anti- inflammatory drugs (NSAIDs) and corticosteroids (glucocorticoids).
[00261] NSAIDs include, but are not limited to: aspirin, salicylic acid, gentisic acid, choline magnesium salicylate, choline salicylate, choline magnesium salicylate, choline salicylate, magnesium salicylate, sodium salicylate, diflunisal, carprofen, fenoprofen, fenoprofen calcium, flurobiprofen, ibuprofen, ketoprofen, nabutone, ketolorac, ketorolac tromethamine, naproxen, oxaprozin, diclofenac, etodolac, indomethacin, sulindac, tolmetin, meclofenamate, meclofenamate sodium, mefenamic acid, piroxicam, meloxicam, COX-2 specific inhibitors (such as, but not limited to, celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib, lumiracoxib, CS-502, JTE-522, L- 745,337 and NS398).
[00262] Corticosteroids, include, but are not limited to: betamethasone, prednisone, alclometasone, aldosterone, amcinonide, beclometasone, betamethasone, budesonide, ciclesonide, clobetasol, clobetasone, clocortolone, cloprednol, cortisone, cortivazol, deflazacort, deoxycorticosterone, desonide, desoximetasone, desoxycortone, dexamethasone, diflorasone, diflucortolone, difluprednate, fluclorolone, fludrocortisone, fludroxycortide, flumetasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin, fluocortolone, fluorometholone, fluperolone, fluprednidene, fluticasone, formocortal, halcinonide, halometasone, hydrocortisone/cortisol, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone butyrate, loteprednol, medrysone, meprednisone, methylprednisolone, methylprednisolone aceponate, mometasone furoate, paramethasone, prednicarbate, prednisone/prednisolone, rimexolone, tixocortol, triamcinolone, and ulobetasol.
[00263] In one embodiment, a LPA receptor antagonist is administered in combination with leukotriene receptor antagonists including, but are not limited to, BAY u9773 (see EP 00791576), DUO-LT (Tsuji et al, Org. Biomol. Chem., 1, 3139-3141, 2003), zafirlukast, montelukast, prankulast, and derivatives or analogs thereof.
[00264] In some embodiments, an LPA receptor antagonist is administered in combination with agents to increase blood flow, including nifedipine, amlodipine, diltiazem, felodipine, or nicardipine.
[00265] In some embodiments, an LPA receptor antagonist is administered in combination with methotrexate, cyclophosphamide, azathioprine, or mycophenolate.
[00266] In some embodiments, an LPA receptor antagonist is administered in combination with pirfenidone.
[00267] In some embodiments, the LPA antagonist and the additional therapeutic agent are in the same pharmaceutical composition. In some embodiments, the LPA receptor antagonist and the additional therapeutic agent are in separate pharmaceutical compositions. In some embodiments, the LPA receptor antagonist and the additional therapeutic agent are in separate pharmaceutical compositions wherein the LPA receptor antagonist is administered by inhalation and the additional therapeutic agent is administered by the same route or by a different route. In some embodiments, the LPA receptor antagonist and the additional therapeutic agent are administered at the same time. In some embodiments, the LPA receptor antagonist and the additional therapeutic agent are administered at different times.
EXAMPLES
[00268] These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.
Example 1: Inhalable solution formulation (preservative free)
LPA receptor antagonist | 500 mg Anhydrous Citric Acid 100 mg
Sodium Chloride 800 mg
Sterile water for inhalation 100 mL
[00269] LPA receptor antagonist, citric acid and sodium chloride are dissolved in water and the solution is filtered through a 0.2 μ filter system and packaged in sterile metered spray bottles.
Example 2: Inhalable solution formulation with preservative
Figure imgf000052_0001
[00270] LPA receptor antagonist, and sodium chloride are dissolved in water, hydrochloric acid and benzalkonium chloride are added. The solution is filtered through a 0.2 μ filter system and packaged in sterile metered spray bottles.
Example 3: Inhalable suspension formulation
Figure imgf000052_0002
[00271] LPA receptor antagonist is suspended in water, Span 85 is added followed by addition of dextrose and ascorbic acid. Benzalkonium chloride is added and the pH is adjusted to 7 with phosphate buffer. The suspension is packaged in sterile nebulizers.
Example 4: Inhalable emulsion formulation for aerosols
Figure imgf000052_0003
[00272] LPA receptor antagonist is suspended in HFC-227, ethyl alcohol is added followed by addition of Span 85 and ascorbic acid. The pH is adjusted to 7 with phosphate buffer. The emulsion is packaged in sterile aerosol metered spray bottles.
Example 5: Dry powder formulation
[00273] LPA receptor antagonist (50 g) is jet milled to obtain a median particle size diameter of 3-4 μηι. Lactose (5 kg) is jet milled to a median particle size diameter of 5 μηι. The ingredients are mixed in a blender bowl at 40-50 rpm and the final mixture is packaged in sterile insufflators.
Example 6. Establishment of a CHO Cell Line Stably Expressing Human LPA^ [00274] A 1.1 kb cDNA encoding the human LPAi receptor was cloned from human lung. Human lung RNA (Clontech Laboratories, Inc. USA) was reverse transcribed using the RETROscript kit (Ambion, Inc.) and the full-length cDNA for human LPAi was obtained by PCR of the reverse transcription reaction. The nucleotide sequence of the cloned human LPAi was determined by sequencing and confirmed to be identical to the published human LPAi sequence (An et al. Biochem. Biophys. Res. Commun. 231 :619 (1997). The cDNA was cloned into the pCDNA5/FRT expression plasmid and transfected in CHO cells using lipofectamine 2000 (Invitrogen Corp., USA). Clones stably expressing human LPAi were selected using hygromycin and identified as cells that show Ca- influx in response to LPA.
Example 7. Generation of Cells Transiently Expressing Human hLPA?
[00275] An expression vector encoding thehuman LPA2 cDNA was transiently transfected into B103 cells using Lipofectamine™ 2000 (Invitrogen) following the manufacturers instruction. On the day before the assay, 30,000-35,000 cells/well were seeded together with 0.2 μΐ lipofectamine 2000 and 0.2 μg human LPA2 expression vector in 96-well Poly-D-Lysine coated black-wall clear-bottom plates (BD BioCoat) in DMEM + 10% FBS. Following an overnight culture, cells were washed once with PBS then cultured in serum-free media for 4 hours prior to start of the calcium flux assay.
Example 8. Establishment of a CHO Cell Line Stably Expressing Human LPA
[00276] A vector containing the human LPA3 receptor cDNA was obtained from the Missouri S&T cDNA Resource Center (www.cdna.org). The full-length cDNA fragment for human LPA3 was obtained by PCR from the vector. The nucleotide sequence of the cloned human LPA3 was determined by sequencing and confirmed to be identical to the published human LPA3 sequence (NCBI accession number NM_012152). The cDNA was cloned into the pCDNA5/FRT expression plasmid and transfected in CHO cells using lipofectamine 2000 (Invitrogen Corp., USA). Clones stably expressing human LPA3 were selected using hygromycin and identified as cells that show Ca- influx in response to LPA.
Example 9. LPAI and LPA3 Calcium Flux Assays.
[00277] Human LPAi or LPA3 expressing CHO cells are seeded at 20,000-45,000 cells per well in a 96-well poly-D-lysine coated plate one or two days before the assay. Prior to the assay, the cells are washed once with PBS and then cultured in serum- free media for at least 6 hrs and up to 24hrs . On the day of the assay, a calcium indicator dye (Calcium 5, Molecular Devices) in assay buffer (HBSS with Ca2+ and Mg2+ and containing 20 mM Hepes and 0.3%) fatty-acid free human serum albumin) is added to each well and incubation continued for 1 hour at room temperature. 10 μΐ of test compounds in 2.5%o DMSO are added to the cells and incubation continued at room temperature for 30 minutes. Cells are the stimulated by the addition of 10 nM LPA and intracellular Ca2+ measured using the Flexstation 3 (Molecular Devices). IC50s are determined using Symyx Assay Explorer analysis of drug titration curves. Example 10. LPA2 Calcium Flux Assay.
[00278] LPA2 calcium flux is measured using at least one of two different assays. In one assay, BT- 20 human breast cancer cells are seeded at 25,000-35,000 cells per well in 150 μΐ complete media on Poly-D-Lysine coated black-wall clear-bottom plates. Following an overnight culture, cells are washed once with PBS then serum starved for 4-6 hours prior to the assay. On the day of the assay, a calcium indicator dye (Calcium 5, Molecular Devices) in assay buffer (HBSS with Ca2+ and Mg2+ and containing 20 mM Hepes and 0.3% fatty-acid free human serum albumin) is added to each well and incubation continued for 15 minutes at 37°C. 25 μΐ of test compounds in 2.5% DMSO are added to the cells and incubation continued at 37°C for 15-30 minutes. Cells are the stimulated by the addition of 100 nM LPA and intracellular Ca2+ measured using the Flexstation 3 (Molecular
Devices). IC50S are determined using Symyx Assay Explorer analysis of drug titration curves In the second assay, B 103 cells transiently expressing huma LPA2 are serum starved for 4 hours. A calcium indicator dye (Calcium 4, Molecular Devices) in assay buffer (HBSS with Ca2+ and Mg2+ and containing 20 mM Hepes and 03% fatty-acid free human serum albumin) is then added to each well and incubation continued for 1 hour at 37°C. 10 μΐ of test compounds in 2.5% DMSO are added to the cells and incubation continued at room temperature for 30 minutes. Cells are the stimulated by the addition of 10 nM LPA and intracellular Ca2+ measured using the Flexstation 3 (Molecular Devices). IC50s are determined using Symyx Assay Explorer analysis of drug titration curves.
Example 11. GTPyS Binding Assay
[00279] The ability of a compound to inhibit binding of GTP to LPAi is assessed via a membrane [35S]-GTPyS binding assay. CHO cells stably expressing the recombinant human LPAi receptor are resuspended in 10 mM Hepes, 7.4 containing 1 mM DTT, lysed and centrifuged at 75,000 xg to pellet the membranes. The membranes are resuspended in 10 mM Hepes, 7.4 containing 1 mM DTT and 10%) glycerol. Membranes (~25 μg per well) are incubated in 96-well plates with 0.1 nM [35S]- GTPyS, 900 nM LPA, 5 μΜ GDP, and test compound in Assay Buffer (50 mM Hepes, pH 7.4, 100 mM NaCl, 10 mM MgCl2 , 50 μg/ml saponin and 0.2%> fatty-acid free human serum albumin) for 30 minutes at 30°C. The reactions are terminated by rapid filtration through Whatman GF/B glass fibre filter plates. The filter plates are washed 3 times with 1 ml cold Wash Buffer (50 mM Hepes, 7.5, 100 mM NaCl and 10 mM MgC^) and dried. Scintillant is then added to the plates and the radioactivity retained on the filters is determined on a Packard TopCount (Perkin Elmer). Specific binding is determined as total radioactive binding minus non-specific binding in the absence of the ligand (900 nM LPA). IC50s were determined using Graphpad prism analysis of drug titration curves.
[00280] Illustrative in vitro biological data is presented in the Table below.
Figure imgf000054_0001
Figure imgf000055_0001
A= less than 0.2uM , B= 0.2-1.0uM, and C= greater than luM; ND = assay not performed
Example 12. LPAI Chemotaxis Assay.
[00281] Chemotaxis of the A2058 human melanoma cells was measured using the Neuroprobe ChemoTx® System plates (8 μηι pore size, 5.7 mm diameter sites). The filter sites were coated with 0.001% fibronectin (Sigma) in 20 mM Hepes, pH 7.4 and allowed to dry. A2058 cells were serum- starved for 24 hours , then harvested with Cell Stripper and resuspended in DMEM containing 0.1% fatty-acid- free bovine serum albumin (BSA) to a concentration of 1 x 106/ml. Cells were mixed with an equal volume of test compound (2X) in DMEM containing 0.1% fatty-acid- free BSA and incubated at 37°C for 15 minutes. LP A (100 nM in DMEM containing 0.1% fatty-acid-free BSA) or vehicle was added to each well of the lower chamber and 50 μΐ of the cell suspension/test compound mix was applied to the upper portion of the ChemoTx plate. Plates were incubated at 37°C for three hours and then the cells removed from the upper portion by rinsing with PBS and scraping. The filter was dried then stained with HEMA 3 Staining System (Fisher Scientific). The absorbance of the filter was read at 590 nM and IC50s were determined using Symyx Assay Explorer.
[00282] In this experiment, Compound A inhibited LPA-driven chemotaxis (IC50 less than 300 nM) of human A2058 melanoma cells.
[00283] In this experiment, compound B inhibited LPA-driven chemotaxis (IC50 less than 100 nM) of human A2058 melanoma cells.
Example 13: Bleomycin-induced Lung fibrosis model in mice
[00284] Female C57B1/6 mice (Harlan, 25-30g) are housed 4 per cage, given free access to food and water and allowed to acclimate for at least 7 days prior to test initiation. After the habituation phase, mice are lightly anesthetized with isoflurane (5% in 100% 02) and administered with bleomycin sulfate (0.01-5 U/kg, Henry Schein) via intratracheal instillation (Cuzzocrea S et al. Am J Physiol Lung Cell Mol Physiol. 2007 May;292(5):L1095-104. Epub 2007 Jan 12.). Mice are returned to their cages and monitored daily for the duration of the experiment. Test compound or vehicle is delivered po, ip or sc daily. The route and frequency of dosing is based on previously determined
pharmacokinetic properties. All animals are sacrificed using inhaled isoflurane 3, 7, 14, 21 or 28 days after bleomycin instillation. Following sacrifice, mice are intubated with a 20 gauge angiocatheter attached to a 1 ml syringe. Lungs are lavaged with saline to obtain bronchoalveolar lavage fluid (BALF) and then removed and fixed in 10%) neutral buffered formalin for subsequent histopathological analysis. BALF is centrifuged for 10 min at 800 x g to pellet the cells and the cell supernatant removed and frozen at -80 °C for subsequent protein analysis using the DC protein assay kit (Biorad, Hercules, CA.) and soluble collagen analysis using Sircol (Biocolor Ltd, UK). BALF is analyzed for concentrations of inflammatory, pro-fib rotic and tissue injury biomarkers including transforming growth factor βΐ, hyaluronic acid, tissue inhibitor of metalloproteinase- 1 , matrix matelloproteinase-7, connective tissue growth factor and lactate dehydrogenase activity, using commercially available ELISA. The cell pellet is re-suspended in PBS. Total cell counts are then obtained using a Hemavet hematology system (Drew Scientific, Wayne, PA.) and differential cells counts are determined using Shandon cytospin (Thermo Scientific, Waltham, MA.). Lung tissue is stained using hematoxylin and eosin (H&E) and tri chrome and lung fibrosis. is determined by semiquantitative histopathological scoring (Ashcroft T. et al. J. Clin. Path. 1988;41;4, 467-470) using light microscopy (lOx magnification) and quantitative, computer-assisted densitometry of collagen in lung tissue sections using light microscopy. The data are plotted using Graphpad prism and statistical differences between groups determined.
[00285] Compound A reduced total protein, lactate and TIMP-1 in the BALF in the acute setting (3- day). Compound A decreased inflammatory cell influx and fibrosis after a single bleomycin instillation (3.0 units) in the chronic setting (14-days only).
[00286] In the acute setting (3 day), Compound B significantly reduced total protein and collagen concentrations in broncheoalveolar lavage fluid (BALF). In a 7-day bleomycin model compound B reduced BALF collagen, protein, TGF i, MMP-7, hyaluronan, and inflammatory cell influx. In the chronic setting (14 day bleomycin model), Compound B decreased total lung collagen when dosed either propylactically (day 0 - day 14) or therapeutically (day 3 - day 14).
Example 14: Mouse intravenous LPA-induced histamine release
[00287] A mouse intravenous LPA-induced histamine release model is utilized to determine the in vivo potency of LPAi and LP A3 receptor antagonists. Female CD-I mice (weighing 25 - 35 grams) are administered compound (i.p., s.c. or p.o.) in a volume of lOml/kg 30 minutes to 24 hours prior to intravenous LPA challenge (300 μg/mouse in 0.1% FAF BSA). Immediately following LPA challenge mice are placed into an enclosed Plexiglas chamber and exposed to an isoflurane for a period of 2 minutes. They are removed, decapitated and trunk blood collected into tubes containing EDTA. Blood is then centrifuged at 10,000 X g for 10 minutes at 4°C. Histamine concentrations in the plasma are determined by EIA. Drug concentrations in plasma are determined by mass spectrometry. The dose to achieve 50% inhibition of blood histamine release is calculated by nonlinear regression (Graphpad Prism) and plotted as the ED50. The plasma concentration associated with this dose is plotted as the EC50.
Example 15: Clinical Trial in Humans with Idiopathic Pulmonary Fibrosis (IPF)
Purpose [00288] The purposes of this study is to assess the efficacy of treatment with the inhalable formulation of LPA receptor antagonist compared with placebo in patients with idiopathic pulmonary fibrosis (IPF) and to assess the safety of treatment with the inhalable formulation of LPA receptor antagonist compared with placebo in patients with IPF.
[00289] The primary outcome variable is the absolute change in percent predicted forced vital capacity (FVC) from baseline to Week 72.
[00290] Secondary outcome measures include: composite outcomes of important IPF-related events; progression- free survival; categorical assessment of absolute change in percent predicted FVC from baseline to Week 72; change in Shortness-of-Breath from baseline to Week 72; change in percent predicted hemoglobin (Hb)-corrected carbon monoxide diffusing capacity (DLco) of the lungs from baseline to Week 72; change in oxygen saturation during the 6 minute walk test (6MWT) from baseline to Week 72; change in high-resolution computed tomography (HRCT) assessment from baseline to Week 72; change in distance walked in the 6MWT from baseline to Week 72.
Criteria
[00291] Patients eligible for this study include those patients that satisfy the following inclusion criteria: diagnosis of IPF; 40 to 80 years of age; FVC > 50% predicted value; DLco > 35% predicted value; either FVC or DLco < 90% predicted value; no improvement in past year; able to walk 150 meters in 6 minutes and maintain saturation > 83%) while on no more than 6 L/min supplemental oxygen.
[00292] Patients are excluded from this study if they satisfy any of the following criteria: unable to undergo pulmonary function testing; evidence of significant obstructive lung disease or airway hyper- responsiveness; in the clinical opinion of the investigator, the patient is expected to need and be eligible for a lung transplant within 72 weeks of randomization; active infection; liver disease; cancer or other medical condition likely to result in death within 2 years; diabetes; pregnancy or lactation; substance abuse; personal or family history of long QT syndrome; other IPF treatment; unable to take study medication; withdrawal from other IPF trials.
[00293] Patients are dosed with either placebo or inhalable formulation of LPA receptor antagonist. The primary outcome variable will be the absolute change in percent predicted FVC from Baseline to Week 72. Patients will receive blinded study treatment from the time of randomization until the last patient randomized has been treated for 72 weeks. A Data Monitoring Committee (DMC) will periodically review safety and efficacy data to ensure patient safety.
[00294] After week 72, patients who meet the Progression of Disease (POD) definition, which is a > 10%) absolute decrease in percent predicted FVC or a > 15%o absolute decrease in percent predicted DLco, will be eligible to receive permitted IPF therapies in addition to their blinded study drug. Permitted IPF therapies include corticosteroids, azathioprine, cyclophosphamide and N-acetyl- cysteine. [00295] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.

Claims

WHAT IS CLAIMED IS:
1. An inhalable formulation comprising an LPA receptor antagonist and at least one
pharmaceutically acceptable excipient, wherein the formulation is in a form suitable for administration to the lungs of a mammal.
2. The inhalable formulation of claim 1, wherein the inhalable formulation comprises an LPA receptor antagonist in an amount effective for the treatment of an LPA-dependent or LPA- mediated disease or condition, and the inhalable formulation is in the form of a solution, suspension, emulsion, colloidal dispersion, spray, aerosol, or dry powder.
3. The inhalable formulation of claim 2, wherein the LPA receptor antagonist is an antagonist of one or more LPA receptors selected from LPAl5 LPA2, LPA3, LPA4 and LPA5.
4. The inhalable formulation of claim 3, wherein the LPA receptor antagonist is an LPAi
antagonist.
5. The inhalable formulation of any one of claims 1-4, wherein the LPA receptor antagonist is a compound having the s
Figure imgf000059_0001
Formula (I)
wherein,
Pv1 is -C02H, -C02RD, tetrazolyl, 5-oxo-2,5-dihydro-[l,2,4]oxadiazol-3-yl, -
C(=0)NHS02CH3, or -C(=0)NHS02CH2CH3; RDis -CH3, -CH2CH3, -CH2CH2CH3, - CH(CH3)2, -CH2CH2CH2CH3, or -C(CH3)3;
L1 is Ci-C4alkylene or C3-C6Cycloalkylene;
Pv3 is H, -CH3, -CH2CH3, or -CF3;
Figure imgf000059_0002
CY is Ci-C6alkyl, substituted or unsubstituted C3-C6Cycloalkyl, or substituted or
unsubstituted phenyl; wherein if CY is substituted then CY is substituted with 1 or 2 Rc; each Rc is independently F, CI, Br, I, -OH, -CN, C C4alkyl, C C4fluoroalkyl, C C4fluoroalkoxy, or Ci-C4alkoxy;
or a pharmaceutically acceptable salt thereof.
6. The inhalable formulation of claim 5, wherein the compound of Formula (I) has the following structure:
Figure imgf000060_0001
The inhalable formulation of claim 5, wherein the compound of Formula (I) has the structure of Formula (II):
Figure imgf000060_0002
Formula (II)
wherein,
n is 0, 1, or 2.
The inhalable formulation of any one of claims 5-7, wherein:
L1 is -CH2-, or cyclopropyl-l,l-diyl;
R3 is H or -CH3;
R8 is -CH3.
The inhalable formulation of any one of claims 1-4, wherein the LPA receptor antagonist is: (R)-2-(4'-(3-methyl-4-((l-phenylethoxy)carbonylamino)isoxazol-5-yl)biphenyl-4-yl)acetic acid (Compound A):
(R)-l-(4'-(3-methyl-4-((l-phenylethoxy)carbonylamino)isoxazol-5-yl)biphenyl-4- yl)cyclopropanecarboxylic acid (Compound B):
(R)-2-(4'-(4-((l-(2-chlorophenyl)ethoxy)carbonylamino)-3-methylisoxazol-5-yl)biphenyl-4- yl)acetic acid (Compound C):
{5-[4'-(l-Methanesulfonylaminocarbonyl-cyclopropyl)-biphenyl-4-yl]-3-methyl-isoxazol-4- yl}-carbamic acid (R)- 1 -phenyl-ethyl ester (Compound D):
1 -(4'- (4-[(R)- 1 -(2-Chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl} -biphenyl- 4-yl)-cyclopropanecarboxylic acid (Compound E):
1 - (4'-[4-((R)- 1 -Phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl} - cyclopropanecarboxylic acid (Compound F):
(3-Methyl-5-{4'-[l-(5-oxo-2,5-dihydro-[l,2,4]oxadiazol-3-yl)-cyclopropyl]-biphenyl-4-yl}- isoxazol-4-yl)-carbamic acid (R)- 1 -phenyl-ethyl ester (Compound G); (3-Methyl-5-{4'-[l-(lH-tetrazol-5-yl)-cyclopropyl]-biphenyl-4-yl}-isoxazol-4-yl)-carbamic acid (R)-l-phenyl-ethyl ester (Compound H);
or a pharmaceutically acceptable salt thereof.
The inhalable formulation of any one of claims 1-4, wherein the LPA receptor antagonist has structure of Formula III):
Figure imgf000061_0001
Formula (III)
wherein
Pv1 is -C02H, -C02RD, tetrazolyl, 5-oxo-2,5-dihydro-[l,2,4]oxadiazol-3-yl, -
C(=0)NHS02CH3, or -C(=0)NHS02CH2CH3; RDis -CH3, -CH2CH3, -CH2CH2CH3, - CH(CH3)2, -CH2CH2CH2CH3, or -C(CH3)3;
L1 is absent, or a Ci-C6alkylene;
R3 is H, -CH3, -CH2CH3, or -CF3;
R4 is -NHC(=0)OCH(R8)-CY;
R8 is H, or -CH3;
CY is substituted or unsubstituted phenyl; wherein if CY is substituted then CY is
substituted with 1 or 2 Rc; each Rc is independently F, CI, Br, I, -OH, -CN, C
C4alkyl, Ci-C4fluoroalkyl, Ci-C4fluoroalkoxy, or C C4alkoxy;
or a pharmaceutically acceptable salt thereof.
The inhalable formulation of claims 10, wherein:
R1 is -C02H or -C02RD;
L1 is -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, - CH2CH2CH2-, or -CH2CH2CH2CH2-;
R3 is H or -CH3;
R8 is -CH3.
The inhalable formulation of any one of claims 1-4, wherein the LPA receptor antagonist is 6- (4- {4-[ 1 -(2-Chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl} -phenyl)-hex-5- ynoic acid, or 7-(4-{4-[l-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}- phenyl)-hept-6-ynoic acid, or a pharmaceutically acceptable salt thereof
The inhalable formulation of any one of claims 1-4, wherein the LPA receptor antagonist has the structure of Formula (IV):
Figure imgf000061_0002
Formula (IV) wherein,
A is an aryl or heteroaryl ring;
R3 is H, Ci-C4alkyl, Ci-C4fmoroalkyl;
R4 is -NHC(=0)OCH(R8)-CY, or -NHC(=0)0-CY;
R8 is H, Ci-C4alkyl, Ci-C4fmoroalkyl;
CY is a substituted or unsubstituted C3-C6cycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic heteroaryl; wherein if CY is substituted then CY is substituted with 1 or 2 Rc; each Rc is independently selected from F, CI, Br, I, -CN, -OH, C C4alkyl, C C4fiuoroalkyl, d-Qfluoroalkoxy, C C4alkoxy, and Ci-C4heteroalkyl;
R5 and R6 are each independently selected from H, halogen, -CN, -N02, -OH, -OR10, C
C4alkyl, Ci-C4fluoroalkyl, Ci-C4fluoroalkoxy, C C4alkoxy, and Ci-C4heteroalkyl; R10 is selected from Ci-C6alkyl, Ci-C6heteroalkyl, Ci-C6fluoroalkyl, a substituted or
unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl;
or a pharmaceutically acceptable salt thereof.
14. The inhalable formulation of claim 13, wherein:
A is phenyl, or a 5- or 6-membered monocyclic heteroaryl;
R5 and R6 are each independently selected from hydrogen, halogen, or hydroxy;
R3 is methyl, ethyl, isopropyl or trifluoromethyl;
R8 is -CH3;
CY is a substituted or unsubstituted phenyl; wherein if CY is substituted then CY is
substituted with 1 or 2 Rc.
15. The inhalable formulation of an one of claims 1-4, wherein the LPA receptor antagonist is:
Figure imgf000062_0001
thereof. The inhalable formulation of any one of claims 1-4, wherein the LPA receptor antagonist has the structure of Formula (V):
Figure imgf000063_0001
Formula (V) wherein,
A is an aryl or heteroaryl ring;
B is an aryl or heteroaryl ring;
L is absent, C C4alkylene, Ci-C4heteroalkylene, -0-, -S-, -SO-, -S02-, -NH-, -NR2-, or -
C(=0)-; R2 is CrQalkyl;
R3 is H, Ci-C4alkyl, or Ci-C4fluoroalkyl;
R4 is -NHC(=0)OCH(R8)-CY, or -NHC(=0)0-CY;
R8 is H, Ci-C4alkyl, or Ci-C4fluoroalkyl;
CY is a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted
heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; wherein if CY is substituted then CY is substituted with 1 or 2 Rc; each Rc is independently selected from F, CI, Br, I, -CN, -OH, C C4alkyl, C
C4fluoroalkyl, Ci-C4fluoroalkoxy, Ci-C4alkoxy, and Ci-C4heteroalkyl;
R5 and R6 are each independently selected from H, halogen, -CN, -N02, -OH, -OR10, C
C4alkyl, Ci-C4fluoroalkyl, Ci-C4fluoroalkoxy, Ci-C4alkoxy, and Ci-C4heteroalkyl;
R5a and R6a are each independently selected from H, halogen, -CN, -N02, -OH, -OR10, - S(=0)2R10, substituted or unsubstituted Ci-C4alkyl, Ci-C4fluoroalkyl, Ci-C4fluoroalkoxy, Ci-C4alkoxy, Ci-C4heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl or substituted or unsubstituted Ci-C6heterocycloalkyl;
R10 is selected from Ci-C6alkyl, Ci-C6heteroalkyl, Ci-C6fluoroalkyl, a substituted or
unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl;
or a pharmaceutically acceptable salt thereof.
The inhalable formulation of claim 16, wherein:
ring A is a substituted or unsubstituted monocyclic ar l or substituted or unsubstituted
monocyclic heteroaryl ring ring wherein the groups
Figure imgf000063_0002
1,3 -relationship on ring A (i.e. an meta relationship) or in a 1 ,4-relationship on ring A (i.e. an para relationship);
R5 and R6 are each independently selected from hydrogen, halogen, or hydroxy;
R5a and R6a are each independently selected from hydrogen, halogen, hydroxy,
hydroxymethyl or substituted or unsubstituted monocyclic heterocycloalkyl;
R3 is methyl, ethyl, isopropyl or trifluoromethyl;
R8 is -C¾;
L is absent, -CH2-, -CH20-, -OCH2-, -CH2S-, -SCH2-, -CH2NH-, -NHCH2-, -0-, -S-, or -NH-. The inhalable formulation of any one of claims 1-4, wherein the LPA receptor antagonist is:
Figure imgf000064_0001
Figure imgf000065_0001
or a pharmaceutically acceptable salt thereof.
The inhalable formulation of any one of claims 1-4, wherein the LPA receptor antagonist has the structure of Formula (VI :
Figure imgf000065_0002
Formula (VI)
R1 is -C02RD, -C(=0)NHS02RE, -C(=0)N(RD)2, or tetrazolyl;
RD is H or Ci-C6alkyl;
RE is Ci-C6alkyl, C3-C6cycloalkyl, or substituted or unsubstituted phenyl;
L3 is a substituted or unsubstituted C3-C6alkylene, a substituted or unsubstituted C3-
C6fiuoroalkylene, or a substituted or unsubstituted C3-C6heteroalkylene, where if L3 is substituted then L3 is substituted with 1, 2 or 3 R13; each R13 is independently F, C
C4alkyl, Ci-C4fluoroalkyl, or -OH;
each Rc is independently halogen, -CN, -N02, -OH, Ci-C4alkyl, Ci-C4fluoroalkyl, Ci-
C4fluoroalkoxy, Ci-C4alkoxy, or Ci-C4heteroalkyl;
R3 is H or Ci-C4alkyl;
n is 0, 1, or 2;
or a pharmaceutically acceptable salt thereof.
The inhalable formulation of claim 19, wherein:
R1 is -C02RD, or -C(=0)NHS02RE;
RD is H or C C4alkyl;
RE is Ci-C4alkyl;
L3 is a substituted or unsubstituted C3-C4alkylene, a substituted or unsubstituted C3-
C4fluoroalkylene, or a substituted or unsubstituted C3-C6heteroalkylene; where if L3 is substituted then L3 is substituted with 1, 2 or 3 R13; each R13 is independently selected from F, -CH3, -CH2CH3, -CF3, and -OH;
R3 is -H, -CH3 or -CH2CH3. The inhalable formulation of any one of claims 1-4, wherein the LPA receptor antagonist has the structure of Formula (VII):
Figure imgf000066_0001
Formula (VII)
wherein,
Pv1 is -C02RD, -C(=0)NHS02RE, -C(=0)N(RD)2, -CN, or tetrazolyl;
RDis H or C C6 alkyl;
RE is Ci-C6 alkyl or a substituted or unsubstituted phenyl;
L2 is absent, -C(=0)-, -N(RD)-, substituted or unsubstituted C1-C4 alkylene, or substituted or unsubstituted Ci-C4heteroalkylene, where if L2 is substituted, then L2 is substituted with R12, where R12 is F, C C4alkyl, -OH, or -ORD;
ring A is a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic
Ci-C5heteroarylene, where if ring A is substituted, then ring A is substituted with 1 or 2
R14, each R14 is independently selected from halogen, -CN, -OH, Ci-C4alkyl, Ci-
C4fluoroalkyl, Ci-C4fluoroalkoxy, Ci-C4alkoxy, and Ci-C4heteroalkyl;
L4 is absent, or a substituted or unsubstituted C1-C4 alkylene, where if L4 is substituted then
L4 is substituted with R13, where R13 is F, C C4alkyl, -OH, or -ORD;
R3 is H or Ci-C4 alkyl;
each Rc is independently selected from halogen, -CN, -OH, Ci-C4alkyl, Ci-C4fluoroalkyl, C
C4fluoroalkoxy, Ci-C4alkoxy, and Ci-C4heteroalkyl;
n is 0, 1 or 2;
or a pharmaceutically acceptable salt thereof.
The inhalable formulation of claim 21, wherein:
R1 is -C02RD, or -C(=0)NHS02RE;
RD is H or C1-C4 alkyl;
RE is C1-C4 alkyl;
L2 is -CH2-, -CH(CH3)-, or -CH(OH)-;
ring A is a substituted or unsubstituted 5-membered monocyclic Ci-C4heteroarylene
containing 1-4 N atoms, 0 or 1 O atoms and 0 or 1 S atoms, where if ring A is substituted, then ring A is substituted with R14;
L4 is -CH2- or -CH(CH3)-; p is 0 or 1.
The inhalable formulation of claim 21, wherein:
R1 is -C02RD, or -C(=0)NHS02RE;
RD is H or CrC4alkyl;
RE is Ci-C4alkyl;
L2 is -NH-, -CH2-, -CH(CH3)-, -CH(OH)-, -NHCH2- or -NHCH(CH3)-;
ring A is a substituted or unsubstituted 6-membered monocyclic C3-C5heteroarylene
containing 1-3 N atoms, where if ring A is substituted, then ring A is substituted with R14; L4 is absent, -CH2-, or -CH(CH3)-;
p is 0 or 1.
The inhalable formulation of any one of claims 1-23, wherein the at least one
pharmaceutically acceptable excipient comprises at least one pharmaceutically acceptable excipient selected from pH-modifying agents, tonicity agents, propellants, preservatives, and surfactants.
The inhalable formulation of any one of claims 1-24, wherein the inhalable formulation is administered with an atomizer, an insufflator, a nebulizer, a vaporizer, or a metered dose inhaler.
The inhalable formulation of any one of claims 2-25, wherein the LPA-dependent or LPA- mediated disease or condition is lung cancer, asthma, obstructive pulmonary disease (COPD), pulmonary fibrosis, idiopathic pulmonary fibrosis, radiation induced fibrosis, silicosis, asbestos induced pulmonary or pleural fibrosis, acute lung injury, acute respiratory distress syndrome (ARDS), usual interstitial pneumonia (UIP), cystic fibrosis, Chronic lymphocytic leukemia (CLL)-associated fibrosis, Hamman-Rich syndrome, Caplan syndrome, coal worker's pneumoconiosis, cryptogenic fibrosing alveolitis, obliterative bronchiolitis, chronic bronchitis, emphysema, Wegner's granulamatosis, lung scleroderma, or interstitial lung disease.
The inhalable formulation of any one of claims 2-25, wherein the LPA-dependent or LPA- mediated disease or condition is lung cancer, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), usual interstitial pneumonia (UIP), cystic fibrosis, Chronic lymphocytic leukemia (CLL)-associated fibrosis, Hamman-Rich syndrome, Caplan syndrome, coal worker's pneumoconiosis, silicosis, interstitial lung disease, asbestos induced pulmonary or pleural fibrosis, cryptogenic fibrosing alveolitis, or obliterative bronchiolitis.
A method of treating of an LPA-dependent or LPA-mediated disease or condition, comprising administering to a mammal in need thereof a therapeutically-effective amount of an inhalable formulation of any of claims 1-27.
29. The method of claim 28, wherein the LPA-dependent or LPA-mediated disease or condition is lung cancer, asthma, obstructive pulmonary disease (COPD), pulmonary fibrosis, idiopathic pulmonary fibrosis, radiation induced fibrosis, silicosis, asbestos induced pulmonary or pleural fibrosis, acute lung injury, acute respiratory distress syndrome (ARDS), usual interstitial pneumonia (UIP), cystic fibrosis, Chronic lymphocytic leukemia (CLL)- associated fibrosis, Hamman-Rich syndrome, Caplan syndrome, coal worker's
pneumoconiosis, cryptogenic fibrosing alveolitis, obliterative bronchiolitis, chronic bronchitis, emphysema, Wegner's granulamatosis, lung scleroderma, or interstitial lung disease.
30. The method of claim 28, wherein the the LPA-dependent or LPA-mediated disease or
condition is lung cancer, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), usual interstitial pneumonia (UIP), cystic fibrosis, Chronic lymphocytic leukemia (CLL)-associated fibrosis, Hamman-Rich syndrome, Caplan syndrome, coal worker's pneumoconiosis, silicosis, interstitial lung disease, asbestos induced pulmonary or pleural fibrosis, cryptogenic fibrosing alveolitis, or obliterative bronchiolitis.
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