WO2018014017A1 - Substance et procédé de traitement de la fibrose pulmonaire idiopathique et de maladies pulmonaires interstitielles associées - Google Patents

Substance et procédé de traitement de la fibrose pulmonaire idiopathique et de maladies pulmonaires interstitielles associées Download PDF

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Publication number
WO2018014017A1
WO2018014017A1 PCT/US2017/042337 US2017042337W WO2018014017A1 WO 2018014017 A1 WO2018014017 A1 WO 2018014017A1 US 2017042337 W US2017042337 W US 2017042337W WO 2018014017 A1 WO2018014017 A1 WO 2018014017A1
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WIPO (PCT)
Prior art keywords
substance
met
sar
administering
pulmonary fibrosis
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PCT/US2017/042337
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English (en)
Inventor
Michael K. Wilhelm
Hal N. SIEGEL
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New Amsterdam Sciences
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/046—Tachykinins, e.g. eledoisins, substance P; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/193—Colony stimulating factors [CSF]

Definitions

  • the present invention pertains to compounds and methods that have utility for treating and/or mitigating the effects of idiopathic pulmonary fibrosis and related interstitial lung diseases.
  • Pulmonary fibrosis is one of a family of related diseases called interstitial lung diseases that can result in lung scarring. As the lung tissue becomes scarred, it interferes with a person's ability to breathe. Idiopathic pulmonary fibrosis (IPF) is a chronic and ultimately fatal disease in which the patient experiences progressive scarring of lung tissue with no apparent source or cause for the scarring. In PF, as scarring progresses, the sufferers can experience increasingly worsening symptom such as shortness of breath, coughing, fatigue and pain as well as concomitant psychological effects. Individuals suffering from pulmonary fibrotic diseases such as IPF can often manifest a histological pattern known as usual interstitial pneumonia (UIP). UIP can also occur due to diseases such as systemic sclerosis, rheumatoid arthritis, and asbestosis. UIP typically progresses to respiratory failure and death with median survival rates currently being between 3 and 4 years.
  • IPF interstitial pneumonia
  • IPF is one of a larger group of interstitial lung diseases (ILD), characterized by involvement of the lung interstitium. While such diseases affect the interstitium, there can and is involvement of the air sacs, peripheral airways and various vessels.
  • IPF interstitial lung diseases
  • a disease is typically diagnosed as IPF when no cause can be associated with the onset of the disease.
  • Other interstitial lung diseases include diseases like sarcoidosis, anti synthetase syndrome.
  • environmentally induced interstitial lung diseases can include exposure to inhaled substances like silicon and beryllium as well as various organic materials. It is also believed that ILDs can be the result of or associated with various autoimmune diseases such as rheumatoid arthritis, systemic sclerosis and systemic lupus.
  • the interstitial lung disease can be pulmonary fibrosis (PF) such as idiopathic pulmonary fibrosis (IPF).
  • PF pulmonary fibrosis
  • IPF idiopathic pulmonary fibrosis
  • the therapeutic compound is integrated into a dose form that can be administered at least once to a patient to address at least one symptom associated with interstitial lung disease.
  • the therapeutic compound disclosed herein can be administered alone in certain embodiments, or in combination with one or more active agents.
  • a method for treating individuals at risk for developing usual interstitial pneumonia (UIP) and/or individuals presenting ILDs such as IPF at risk of developing an acute exacerbation (AE).
  • the method includes administering an effective amount of a compound selected from the group consisting of [Met-OH u ]-substance P, [Met-OMe u ]-substance P, [Nle u ]-substance P, [Pro 9 ]-substance P, [Sar 9 ]-substance P, [Tyr 8 ]-substance P, Sar 9 , Met (0 2 ) 11 -Substance P, and [p-Cl-Phe 7 8 ]- substance P is administered to the individual on an as needed or continuing basis as part of a treatment regimen.
  • Fig. 1 is a space filling model of Substance P: Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-
  • Fig. 2 is a structural depiction of an analog of Substance P as disclosed herein;
  • Fig. 3 is a table depicting the amino acid sequence for Sar 9 , Met (0 2 ) n - SP and endogenous tachykinins
  • bioactive Substance P analogs including but not limited to Sar 9 , Met (0 2 ) 1 ⁇ Substance P, [Met-OH u ]-substance P, [Met-OMe u ]-substance P, [Nle u ]-substance P, [Pro 9 ] -sub stance P, [Sar 9 ] -sub stance P, [Tyr 8 ]-substance P, and [p-Cl- Phe 7 ' 8 ]-substance P provide therapeutic effect when administered to individuals presenting with various forms of interstitial lung disease (ILD) including, but not limited to, idiopathic pulmonary fibrosis (IPF).
  • ILD interstitial lung disease
  • IPF idiopathic pulmonary fibrosis
  • a bioactive analog of Substance P (RPKPQQFFGLM- H 2 ; SEQ ID NO: 1) can be administered to treat various forms of interstitial lung disease (ILD) manifesting at least one fibrotic mass including, but not limited to, idiopathic pulmonary fibrosis (IPF).
  • ILD interstitial lung disease
  • IPF idiopathic pulmonary fibrosis
  • Non-limiting examples of the bioactive analogs of Substance P that can be employed in the present disclosure include [Met-OH u ]-substance P, [Met-OMe u ]-substance P, [Nle u ]-substance P, [Pro 9 ] -substance P, [Sar 9 ]-substance P, [Tyr 8 ]-substance P, Sar 9 Met (0 2 ) u -Substance P, and [p-Cl-Phe 7 8 ]- substance P.
  • bioactive analogs of Substance P as described herein can be co-administered with Substance P in a suitable treatment regimen.
  • Bioactive analogs of substance P as disclosed herein can be administered by any method known in the art, including via aerosol inhalation. Intravenous, intratracheal, intrabronchial, intramuscular, sublingual, and oral administrations can also be used.
  • Contemplated intravenous dosages include 0.05 to 5 nanomolar compound for intravenous administration. In certain intravenous applications a dose concentration of 0.1 to 2 nanomolar may be employed; while in other applications 0.5 to 1.5 nanomolar concentrations can be used.
  • contemplated dosages include 0.05 to 5.0 micromolar substance P or analog with dosages from 0.1 to 2 micromolar employed in certain applications and dosages from 0.5 to 1.5 micromolar employed in others. Typical concentration ranges of substance P or its bioactive analog in the aerosol administered is between 0.001 and 10 ⁇ . It can be advantageously administered as a liquid at a concentration between about 0.1 and 10 ⁇ .
  • Bioactive analogs are those which act as competitive inhibitors of Substance P by binding to the Substance P receptor (NK-1 receptor).
  • the analogs may be agonists of the NK-1 receptor.
  • Other derivatives as are known in the art and commercially available (e.g., from Sigma) can be used.
  • substance P fragments and derivatized substance P fragments may also be used. Substitution, deletion, or insertion of one to eight amino acid residues, and preferably from one to three amino acid residues, will lead to analogs which can be routinely tested for biological activity.
  • functional groups may be modified on SP while retaining the same amino acid backbone. Again, routine testing will determine which of such modifications do not adversely affect biological activity.
  • Substance P the parent compound for the various analogs disclosed herein, is a relatively small (1,348 Daltons), endogenous peptide first discovered in 1931 and characterized chemically about 40 years later.
  • Neuropeptides such as Substacne P, were originally discovered as being distributed throughout the peripheral and central nervous systems.
  • Substance P has since been shown to be produced in non-neuronal cells such as human endothelial cells, Leydig cells, enterochromaffin cells, epithelial cells, fibroblasts, keratinocytes, intestinal and airway smooth muscle cells, inflammatory and immune cells, and in cells of the female reproductive system.
  • Substance P has been recognized as a mediator of nonadrenergic, noncholinergic (NANC) excitatory neurotransmission, and as playing a role in the transmission of pain.
  • NANC noncholinergic
  • NK-1, NK-2 and NK-3 neurokinin receptors
  • the neurokinin receptors belong to "family 1" (rhodopsin-like) of the G protein-coupled receptors.
  • the NK-1R consists of seven putative a-helical transmembrane segments, an intracellular carboxyl tail, and an extracellular amino-terminus. At the extracellular amino terminus there is an N- glycosylation site, while many serine and threonine residues at the intracellular carboxyl terminus are potential phosphorylation sites.
  • the Neurokinin-1 receptor has been identified in stem cell lines as well as cells derived from human placental cord blood, rich in hematopoietic stem and progenitor cells.
  • the NK-1R has been identified in a various tissues and cell type and is expressed in immune cells such as T and B lymphocytes, monocytes/macrophages, neutrophils, and mast cells.
  • Non- immune cells like vascular endothelial cells, bone marrow stromal cells, muscle cells, astrocytes, adipocytes, keratinocytes, and fibroblasts also express the K-1R.
  • the NK-1R receptor is appears to be involved in a number of physiological systems that may be of significance to the immune system, and the cells that support the immune system.
  • Substance P analogs including but not limited to Sar 9 , Met (02) U -SP are distinct from the tachykinins Neurokinin A (NKA) and Neurokinin B (NKB) at the N-terminus (referenced by the start of the amino acid sequence as seen in FIG 3. These differences result in NKA and NKB binding with significantly less affinity to the Neurokinin-1 receptor (NK-1R) than do compounds such as Sar 9 , Met (02) U -SP, which share an identical N-terminal sequence.
  • the C-terminal penta-peptide, Phe-Phe/Val-Gly-Leu- Met-NH 2 is conserved between all natural tachykinins and is required for receptor activation.
  • one particular analog that has been found to be particularly efficacious in treatment is created by modifying two of the eleven amino acids in the Substance P sequence. These modifications included replacing glycine (Gly) with sarcosine (Sar or N-methyl glycine) at the ninth position and introducing an oxidized form of methionine
  • Substance P analog binds to all three neurokinin receptors (NK-1, NK-2 and NK-3), though SP preferentially interacts at the NK-IR to mediate its biological effects.
  • 1R induces secondary messenger signaling events, which originate from the activated receptor and then rapidly cascade throughout the cell.
  • Water-soluble messengers like Ca 2+ and cyclic AMP (cAMP), diffuse throughout the cytosol, while the hydrophobic lipid-soluble messengers like diacylglycerol (DAG) diffuse into the plasma membrane.
  • cAMP cyclic AMP
  • DAG diacylglycerol
  • SP analogs disclosed herein such as Sar 9 Met (0 2 ) u -SP are capable of utilizing both phosphatidylinositol (PI) hydrolysis and cAMP as second messenger signaling systems (mediating changes in intracellular Ca 2+ mobilization), and do so with high potency.
  • PI phosphatidylinositol
  • cAMP second messenger signaling systems
  • the Substance P analog, Sar 9 Met (0 2 ) u -SP is a 1393 Da, 11-amino acid, synthetically-manufactured analog of Substance P (SP).
  • Sar 9 Met (0 2 ) u -SP is modified at the 9th [N-Methyl glycine (or Sarcosine) instead of glycine] and 11th (addition of a Sulphone) positions. These modifications render Sar 9 Met (O2) 11 - Sub stance P receptor-specific for the Neurokinin-1 receptor, and also make Sar 9 Met (0 2 ) u -SP more resistant to proteolytic degradation relative to the endogenous peptide, Substance P.
  • ECE-1 endothelin-converting enzyme-1
  • ECE-1 hydrolyzes SP at Gln 6 -Phe 7 and Gly 9 -Leu 10 linkages and degradation of endocytosed neuropeptides regulates trafficking and signaling of internalized receptors.
  • This enzyme facilitates the release of the receptor from the ligand-receptor complex and allows for the receptor to be recycled back to the cell surface, which mediates resensitization.
  • Sar 9 Met (02) U -SP may induce cellular responses that differ from those elicited by SP and reduce the rate at which NK1 receptor recycling and resensitization occurs.
  • the physiological implications of this recent finding are many, and could include a greater initial stimulatory response to K1R stimulation due to the prolonged intracellular kinase activation followed by a prolonged resistance to endogenous SP due to the inhibition of NK1R recycling.
  • bioactive Substance P analogs as disclosed herein have particular applicability and efficiency as a primary or adjunct therapeutic material for treatment of interstitial lung disease (ILD) such as fibrosis, idiopathic pulmonary fibrosis, as well as prodromal conditions which present prior to the onset of ILD.
  • ILD interstitial lung disease
  • a therapy regimen that includes administration of the compounds disclosed herein can reduce the incidence and severity of acute exacerbations of PF or IPE
  • one or more of the compounds disclosed herein can be used as an intervention material, alone or in combination with other therapeutic agents in addressing and ameliorating episodes of acute respiratory distress.
  • Suitable analogues include but are not limited to [Met-OH u ]-substance P, [Met-OMe u ]-substance P, [Nle u ]-substance P, [Pro 9 ] -substance P, [Sar 9 ]-substance P, [Tyr 8 ]- substance P, Sar 9 , Met (02) U -Substance P, and [p-Cl-Phe 7 ' 8 ]-substance P.
  • the material can be administered in a concentration sufficient to achieve at least one bioactive effect in the patient.
  • Bioactive affect as the term is employed herein, is taken to mean a dose response exhibited in an average of 50% of the symptomatic or pre-symptomatic patients treated. Dose response as defined herein can include at least one of the following:
  • Short term dose response can be determined based on one or more of the following: increased lung capacity expressed as vital capacity or forced vital capacity, improved static lung volume, improved lung histopathology expressed as interstitial pathology and/or alveolitis; decreased dyspnea on exertion and increases in functional exercise tolerance, increase in the diffusing capacity for carbon monoxide (DLco), decreased evidence of oxygen
  • vitamin capacity is defined as the maximum amount of air a person can expel from the lungs after a maximum inhalation. It is equal to the sum of inspiratory reserve volume, tidal volume, and expiratory reserve volume.
  • FVC Forced vital capacity
  • Static lung volume is defined as the measurement of total lung capacity (TLC), residual volume (RV), functional residual capacity (FRC), and vital capacity (VC).
  • Functional exercise tolerance in humans can be measured using a six-minute walk test (6MWT) as developed by Balke and promulgated by the American College of Rheumatology.
  • 6MWT six-minute walk test
  • "Diffusing capacity of the lungs for carbon monoxide” as used herein is a determination of how much oxygen travels from the alveoli of the lungs to the blood stream.
  • the material disclosed herein can be formulated as an aerosolizable fluid with active component present in an amount between 0.1 and 10 ⁇ . It is also contemplated that the active component can be formulated as a solid dose form as a pill or tablet or as a powder or granular material. In certain applications in which the dose form employed is a pill or powder, it is contemplated that the bioactive analog of Substance P disclosed herein can be present in the dose form at a concentration between 0.05 to 7 nanomolar. In certain applications, it is contemplated that the active compound disclosed herein can be present at suitable therapeutic concentrations, for example 0.05 to 5 nanomolar.
  • Suitable devices for administering an aerosol as disclosed herein may include nebulizers as well as hand-held aerosol "puffer” devices.
  • Suitable treatment regimens for treatment according to the present invention include daily or multiple daily treatment by aerosol .
  • bioactive analogs of substance P for administration are any which are pharmaceutically acceptable and in which bioactive analogs of substance P retains its biological activity.
  • such formulations include bioactive analogs of substance P dissolved in normal sterile saline.
  • Other formulations for changing absorption and half-life characteristics can be used, including liposomal formulations and slow-release formulations,
  • bioactive analogs of Substance P described herein function as pleotropic agent to reverse the pathologies associated with interstitial lung disease (ILD) particularly fibrotic development as evidenced in idiopathic pulmonary fibrosis as well as pulmonary fibrosis
  • ILD interstitial lung disease
  • mice Twelve animals (C571B1 mice) are subjected to 5 Gy of whole body radiation and with an additional lung dose added of 10 Gy. Exposed animals are sorted into three groups. One group of three is held as a control; another group of three is dosed immediately and for 14 consecutive days following acute radiation exposure with an aerosolized solution containing 5.0 ⁇ concentration of Sar 9 Met (O2) 11 - Sub stance P . An additional cohort of three animals are permitted to develop symptoms for twelve weeks before the fifteen-day treatment cycle involving administration an aerosolized solution containing 5.0 ⁇ concentration of Sar 9 Met (O2) 1 ⁇ Substance P is commenced. A fourth cohort of three animals is similarly treated at 26 weeks post irradiation.
  • Sar 9 Met (O2) 1 ⁇ Substance P cohorts of irradiated animals received a supplementary lOGy lung- -only radiation dose. Animals that received Sar 9 Met (O2) 11 - Sub stance P in an amount of 2mg/kg prior to subsequent exposure, show enhanced preservation of airway progenitor cells, as revealed by expression of the marker protein Club Cell Secretory Protein (CCSP). It is known that CCSP expression is reduced by lung irradiation, so preservation elicited by Sar 9 Met (O2) 1 ⁇ Substance P treatment prior to irradiation is consistent with mitigation of the progenitor cell damage induced by radiation exposure. In contrast animals treated with GCSF, following radiation exposure, demonstrate some protection from the resultant neutropenia typically following acute irradiation, but fail to show the preservative effect on CCSP expression.
  • CCSP Club Cell Secretory Protein

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Abstract

Selon la présente invention, des analogues de substance P sont utiles pour le traitement et la protection contre la fibrose pulmonaire et des maladies et affections associés. Les agents actifs peuvent être administrés par thérapie par inhalation, par voie intraveineuse, par voie intramusculaire, par voie sublinguale ou par d'autres procédés. Des indices de maladie sont réduits par le le traitement.
PCT/US2017/042337 2016-07-15 2017-07-17 Substance et procédé de traitement de la fibrose pulmonaire idiopathique et de maladies pulmonaires interstitielles associées WO2018014017A1 (fr)

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US62/362,856 2016-07-15

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP7484976B2 (ja) 2022-07-29 2024-05-16 Ｔｏｐｐａｎホールディングス株式会社 調光シート、および、スクリーン

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070172447A1 (en) * 2003-05-16 2007-07-26 Kazuhiro Sakurada Agent for preventing and/or treating tissue disruption-accompanied diseases
WO2015168682A1 (fr) * 2014-05-02 2015-11-05 Wilhelm Michael K Substance et méthode pour le traitement de la grippe

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070172447A1 (en) * 2003-05-16 2007-07-26 Kazuhiro Sakurada Agent for preventing and/or treating tissue disruption-accompanied diseases
WO2015168682A1 (fr) * 2014-05-02 2015-11-05 Wilhelm Michael K Substance et méthode pour le traitement de la grippe

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP7484976B2 (ja) 2022-07-29 2024-05-16 Ｔｏｐｐａｎホールディングス株式会社 調光シート、および、スクリーン

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