WO2021061665A1 - Promédicaments agonistes de l'intégrine - Google Patents

Promédicaments agonistes de l'intégrine Download PDF

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Publication number
WO2021061665A1
WO2021061665A1 PCT/US2020/052034 US2020052034W WO2021061665A1 WO 2021061665 A1 WO2021061665 A1 WO 2021061665A1 US 2020052034 W US2020052034 W US 2020052034W WO 2021061665 A1 WO2021061665 A1 WO 2021061665A1
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alkyl
alkylene
independently
compound
alkoxy
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PCT/US2020/052034
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English (en)
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Craig Alan Coburn
Martin W. Rowbottom
Antonio Barbosa
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Gb006, Inc.
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Publication of WO2021061665A1 publication Critical patent/WO2021061665A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Leukocyte activation, migration and recruitment are essential for the immune response to injury and infection, as well as in various inflammatory and autoimmune disorders.
  • the b2 integrins a sub-family of a/b heterodimeric integrin receptors including highly expressed integrin CD11b/CD18, are leukocyte-specific receptors that modulate leukocyte functions including cell adhesion, migration, recruitment and activation.
  • CD11b/CD18 recognizes the complement fragment iC3b, fibrinogen, and ICAM-1 as ligands, among various others.
  • CD11b/CD18 has been implicated in many inflammatory and autoimmune diseases, such as ischemia-reperfusion injury (including acute renal failure and atherosclerosis), lupus, psoriasis, dermatitis, inflammatory bowel disease, Crohn’s disease, rheumatoid arthritis, multiple sclerosis, lupus nephritis, focal segmental glomerulosclerosis, diabetic nephropathy, renal injury, tissue damage, glaucoma, uveitis, ophthalmic conditions, allograft rejection (such as nephropathy), transplantation, graft versus host disease, fibrosis, stroke, pain (including chronic pain), neointimal thickening in response to vascular injury, and the resolution of inflammatory processes.
  • ischemia-reperfusion injury including acute renal failure and atherosclerosis
  • lupus psoriasis
  • dermatitis dermatitis
  • Crohn’s disease rhe
  • Leukocytic b2 integrins also contribute to processes including tumor growth, tumor re-growth, tumor metastases, leukocyte infiltration into tumors, modulation of inflammation, modulation of anti-tumor responses, leukocyte polarization, modification of tumor microenvironment, production of reactive oxygen species, and modulation of a number of pro- and anti-inflammatory genes and proteins in inflammatory cells.
  • Blocking of b2 integrins, including CD11b/CD18, and their ligands has been shown to decrease the severity of inflammatory response in vivo in certain experimental models. However, such blocking agents have had little success in treating inflammatory/autoimmune diseases in humans.
  • compositions and methods have been developed using compounds that activate integrins and reduce recruitment of inflammatory immune cells into tissues by, for example, increasing integrin CD11b/CD18-dependent cell adhesion to immobilized ligands.
  • Leukadherins are a group of such small molecule agonists targeting integrin CD11b/CD18 (Maiguel, et al.2011. Sci. Signal.4:1–14; Park, et al.2007. J. Biomol. Screen.12:406–417; Faridi, et al.2009. Bioorg. Med. Chem. Lett.19:6902–6906.).
  • Leukadherins also reduce leukocyte activation and pro-inflammatory signaling pathways.
  • leukadherin 1 (“LA1;” (Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- ylidene)methyl)furan-2-yl)benzoic acid) has demonstrated particular anti-inflammatory efficacy.
  • LA1 has been shown to reduce recruitment of leukocytes during acute peritonitis in mice, reduce neointimal thickening upon vascular injury in rats, reduce hyperoxia-dependent lung injury, reduce liver fibrosis, reduce renal ischemia/reperfusion injury in mice, increase allograft survival, and enhance liver repair (Jagarapu, et al.2015. Am J Respir Cell Mol Biol. 53: 793-801; Joshi, et al.2016. Blood.127: 2751-2762; Khan, et al.2014. Front. Med. Vol. 1, Art.45; Kopec, et al.2016.
  • LA1 also reduced tumor growth and re-growth. LA1 and uses thereof have been described in U.S. Pat. Nos.9,023,876 and 9,328,105, as well as in International Pat. Appl. Nos. PCT/US2011/034753, PCT/US2013/037548, and PCT/US2016/037067, which patents and applications are incorporated herein by reference in their entirety.
  • the invention provides a compound according to Formula I: or a pharmaceutically acceptable salt thereof, wherein: X is S or O; Y is NR 1a , S, or O; Z is O or NR 1a ; L 1 is a covalent bond, C 1-6 alkylene, 1- to 6-membered heteroalkylene, -C(O)O- (C 1-6 alkylene)-, -C(O)NR 1a -(C 1-6 alkylene)-, -(C 1-6 alkylene)-OC(O)- or -(C 1-6 alkylene)-OC(O)O-; R 1 is C 1-12 alkyl, C 2-12 alkenyl, C 3-12 cycloalkyl, 5- to 12-membered heterocycloalkyl, C 6-12 aryl, or 5- to 12-membered heteroaryl, wherein R 1 is optionally substituted with one or more of –OH, C 1-6
  • the invention provides pharmaceutical formulations containing the compounds described herein in combination with one or more pharmaceutically acceptable excipients.
  • the invention provides methods for treating b2 integrin- mediated conditions, comprising administering to a patient in need thereof, a compound or formulation as described herein.
  • the integrin-mediated condition is acute inflammation, chronic inflammation, chronic kidney disease, neointimal thickening associated with vascular injury, tissue injury, peritonitis, diabetic nephropathy, an autoimmune disease, cancer, glaucoma, graft versus host disease, macular degeneration or uveitis.
  • Alkyl by itself or as part of another substituent, refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated. Alkyl can include any number of carbons, such as C1-2, C 1-3 , C1-4, C1-5, C 1-6 , C1-7, C1-8, C1-9, C1-10, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6.
  • C 1-6 alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc.
  • Alkyl can also refer to alkyl groups having up to 20 carbons atoms, such as, but not limited to heptyl, octyl, nonyl, decyl, etc. Alkyl groups can be substituted or unsubstituted.
  • “Substituted alkyl” groups can be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, nitro, cyano, and alkoxy.
  • “Alkylene” refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated, and linking at least two other groups, i.e., a divalent hydrocarbon radical. The two moieties linked to the alkylene can be linked to the same atom or different atoms of the alkylene group.
  • a straight chain alkylene can be the bivalent radical of -(CH 2 )n-, where n is 1, 2, 3, 4, 5 or 6.
  • alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene and hexylene.
  • Alkylene groups can be substituted or unsubstituted.
  • heteroalkylene refers to an alkylene group wherein one or more non-adjacent carbon atoms are independently replaced with O, S, or NR, where R is H or C 1-6 alkyl
  • Alkoxy by itself or as part of another substituent, refers to a moiety having the formula –OR, wherein R is an alkyl group as defined herein.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, and isopropyloxy [010]
  • Cycloalkyl by itself or as part of another substituent, refers to a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing from 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyl can include any number of carbons, such as C3-6, C4-6, C5-6, C3-8, C4-8, C5-8, C6-8, C3-9, C3-10, C3-11, and C 3-12 .
  • Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl.
  • Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2] bicyclooctane, decahydronaphthalene and adamantane. Cycloalkyl groups can also be partially unsaturated, having one or more double or triple bonds in the ring.
  • Representative cycloalkyl groups that are partially unsaturated include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbornene, and norbornadiene.
  • exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups can be substituted or unsubstituted.
  • “Substituted cycloalkyl” groups can be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, nitro, cyano, and alkoxy.
  • the term “lower cycloalkyl” refers to a cycloalkyl radical having from three to seven carbons including, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • “Aryl,” by itself or as part of another substituent, refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings.
  • Aryl groups can include any suitable number of ring atoms, such as 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, as well as from 6 to 10, 6 to 12, or 6 to 14 ring members.
  • Aryl groups can be monocyclic, fused to form bicyclic (e.g., benzocyclohexyl) or tricyclic groups, or linked by a bond to form a biaryl group.
  • Representative aryl groups include phenyl, naphthyl and biphenyl.
  • Other aryl groups include benzyl, having a methylene linking group.
  • Some aryl groups have from 6 to 12 ring members, such as phenyl, naphthyl or biphenyl.
  • aryl groups have from 6 to 10 ring members, such as phenyl or naphthyl. Some other aryl groups have 6 ring members, such as phenyl.
  • Aryl groups can be substituted or unsubstituted. “Substituted aryl” groups can be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, nitro, cyano, and alkoxy.
  • Heteroaryl by itself or as part of another substituent, refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing the number of carbon atoms indicated (e.g., 5 to 16 carbon ring atoms), where from 1 to 5 of the carbon ring atoms are replaced by a heteroatom such as N, O or S. Additional atoms can also be useful, including, but not limited to, B, Al, Si and P. The heteroatoms can be oxidized to form moieties such as, but not limited to, -S(O)- and -S(O) 2 -.
  • Heteroaryl groups can include any number of carbon ring atoms, such as 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 carbon ring members. Any suitable number of carbon ring atoms can be replaced with heteroatoms, such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5.
  • Heteroaryl groups can have from 5 to 8 carbon ring members (i.e., C 5-8 heteroaryl) where 1 to 4 carbon ring atoms are replaced with heteroatoms; or from 5 to 8 carbon ring members where 1 to 3 carbon ring atoms are replaced with heteroatoms; or from 5 to 6 carbon ring members (i.e., C 5-6 heteroaryl) where 1 to 4 carbon ring atoms are replaced with heteroatoms; or from 5 to 6 ring members where 1 to 3 carbon ring atoms are replaced with heteroatoms.
  • the heteroaryl group can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.
  • heteroaryl groups can also be fused to aromatic ring systems, such as a phenyl ring, to form members including, but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and cinnoline, benzothiophene, and benzofuran.
  • Other heteroaryl groups include heteroaryl rings linked by a bond, such as bipyridine. Heteroaryl groups can be substituted or unsubstituted.
  • “Substituted heteroaryl” groups can be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, nitro, cyano, and alkoxy. [013] The heteroaryl groups can be linked via any position on the ring.
  • pyrrole includes 1-, 2- and 3-pyrrole
  • pyridine includes 2-, 3- and 4-pyridine
  • imidazole includes 1-, 2-, 4- and 5-imidazole
  • pyrazole includes 1-, 3-, 4- and 5-pyrazole
  • triazole includes 1-, 4- and 5-triazole
  • tetrazole includes 1- and 5-tetrazole
  • pyrimidine includes 2-, 4-, 5- and 6- pyrimidine
  • pyridazine includes 3- and 4-pyridazine
  • 1,2,3-triazine includes 4- and 5-triazine
  • 1,2,4-triazine includes 3-, 5- and 6-triazine
  • 1,3,5-triazine includes 2-triazine
  • thiophene includes 2- and 3-thiophene
  • furan includes 2- and 3-furan
  • thiazole includes 2-, 4- and 5-thiazole
  • isothiazole includes 3-, 4- and 5-isothiazole
  • oxazole includes 2-, 4- and 5-
  • heteroaryl groups include those having from 5 to 10 carbon ring members where 1 to 3 carbon ring atoms are replaced with heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, and benzofuran.
  • heteroatoms such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,
  • heteroaryl groups include those having from 5 to 8 carbon ring members where 1 to 3 carbon ring atoms are replaced with heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.
  • heteroatoms such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.
  • heteroaryl groups include those having from 9 to 12 carbon ring members where 1 to 3 carbon ring atoms are replaced with heteroatoms, such as indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, benzofuran and bipyridine.
  • heteroaryl groups include those having from 5 to 6 carbon ring members where 1 to 2 carbon ring atoms are replaced with heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.
  • heteroatoms such as pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.
  • heteroaryl groups include from 5 to 10 carbon ring members wherein carbon ring atoms are replaced with only nitrogen atoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5- isomers), indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, and cinnoline.
  • Other heteroaryl groups include from 5 to 10 carbon ring members wherein carbon ring atoms are replaced with only oxygen atoms, such as furan and benzofuran.
  • heteroaryl groups include from 5 to 10 carbon ring members wherein carbon ring atoms are replaced with only sulfur atoms, such as thiophene and benzothiophene. Still other heteroaryl groups include from 5 to 10 carbon ring members wherein carbon ring atoms are replaced with at least two types of heteroatoms, such as imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiazole, isothiazole, oxazole, isoxazole, quinoxaline, quinazoline, phthalazine, and cinnoline.
  • heteroatoms such as imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers
  • thiazole is
  • Salt refers to acid or base salts of the compounds of the invention.
  • Illustrative examples of pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts.
  • “Pharmaceutically acceptable” is art-recognized and, as used herein to refer to a composition, excipient, adjuvant, or other material and/or dosage form, refers to a substance which, within the scope of sound medical judgment, is suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • Examples of pharmaceutically acceptable bases include, but are not limited to ammonia, L- arginine, calcium hydroxide, choline hydroxide, meglumine, lysine, magnesium hydroxide, potassium hydroxide, sodium hydroxide. It is understood that the pharmaceutically acceptable salts are non-toxic.
  • salts of the acidic compounds of the present invention are salts formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethylammonium, diethylammonium, and tris-(hydroxymethyl)-methyl- ammonium salts.
  • bases namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethylammonium, diethylammonium, and tris-(hydroxymethyl)-methyl- ammonium salts.
  • cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium
  • ammonium salts such as ammonium, trimethylammonium, diethylammonium, and tris-(hydroxymethyl)-methyl- ammonium salts
  • the neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
  • the term “excipient” refers to a substance that aids the administration of an active agent to a subject.
  • pharmaceutically acceptable it is meant that the excipient is compatible with the other ingredients of the formulation and is not deleterious to the recipient thereof.
  • compositions useful in the present invention include, but are not limited to, binders, fillers, disintegrants, lubricants, glidants, coatings, sweeteners, flavors and colors.
  • “Integrin” refers to a non-covalently linked a/b-heterodimeric cell surface receptor that mediates cell adhesion, migration and signaling. Integrins are expressed in a wide range of organisms, including C. elegans, Drosophila sp., amphibians, reptiles, birds, and mammals, including humans.
  • the superfamily of integrins can be subdivided into families, for example, as aV-containing integrins, including aVb3 and aVb5, or the b1-containing integrins, including a5b1 and aVb1.
  • b2 integrin refers to an integrin having a b2-subunit (also referred to as CD18). b2 integrins have distinct a-subunits selected from CD11a, CD11b, CD11c and CD11d. b2 integrins, including highly expressed integrin CD11b/CD18 (also known as Mac-1, CR3 and aMb2), modulate cellular functions, including cell adhesion, migration, recruitment and activation. [025] “b2-mediated,” as used herein to refer to diseases and/or conditions in a patient, means that the disease or condition results (in whole or in part) from a chemical or physical process involving a b2 integrin.
  • b2-mediated diseases and conditions include inflammatory, autoimmune, and neurodegenerative diseases.
  • b2-mediated diseases and conditions include, but are not limited to, ischemia-reperfusion injury (including acute renal failure and atherosclerosis), lupus, inflammatory bowel disease, Crohn’s disease, rheumatoid arthritis, multiple sclerosis, lupus nephritis, focal segmental glomerulosclerosis, renal injury, glaucoma, ophthalmic conditions, allograft rejection (such as nephropathy), transplantation, graft versus host disease, neurological disorders, Alzheimer’s disease, Parkinson’s disease, traumatic brain injury, dermatitis, tissue damage, stroke, neointimal thickening in response to vascular injury, anti-GBM nephritis, pain (including chronic pain), and cancers, including primary tumors and metastatic tumors, such as breast cancer, melanoma, prostate cancer, ovarian cancer, renal cancer, lung cancer, pancre
  • Cancer refers to an abnormal state or condition characterized by rapidly proliferating cell growth. Hyperproliferative and neoplastic disease states may be categorized as pathologic, i.e., characterizing or constituting a disease state, or may be categorized as non-pathologic, i.e., a deviation from normal but not associated with a disease state. In general, a cancer will be associated with the presence of one or more tumors, i.e., abnormal cell masses. The term “tumor” is meant to include all types of cancerous growths or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues, or organs, irrespective of histopathologic type or stage of invasiveness.
  • cancer examples include malignancies of various organ systems, such as lung cancers, breast cancers, thyroid cancers, lymphoid cancers, gastrointestinal cancers, and genito-urinary tract cancers.
  • Cancer can also refer to adenocarcinomas, which include malignancies such as colon cancers, renal-cell carcinoma, prostate cancer and/or testicular tumors, non-small cell carcinoma of the lung, cancer of the small intestine, and cancer of the esophagus.
  • Carcinomas are malignancies of epithelial or endocrine tissues including respiratory system carcinomas, gastrointestinal system carcinomas, genitourinary system carcinomas, testicular carcinomas, breast carcinomas, prostatic carcinomas, endocrine system carcinomas, and melanomas.
  • an “adenocarcinoma” refers to a carcinoma derived from glandular tissue or in which the tumor cells form recognizable glandular structures.
  • a “sarcoma” refers to a malignant tumor of mesenchymal derivation.
  • “Melanoma” refers to a tumor arising from a melanocyte. Melanomas occur most commonly in the skin and are frequently observed to metastasize widely.
  • the term “treating,” as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • a “therapeutically effective amount” is the amount of an integrin agonist prodrug needed to provide a desired level of drug in the tissues, bloodstream, or other physical compartment of a patient, the desired level giving rise to an anticipated physiological response or biological effect when the integrin agonist prodrug is administered by the chosen route of administration. The precise amount will depend upon numerous factors including, for example, the particular integrin agonist; the specific pharmaceutical formulation or delivery device employed; the severity of the disease state; and patient adherence to a treatment regimen. Therapeutically effective amounts of integrin agonist prodrugs can be readily determined by one skilled in the art based upon the information provided herein.
  • “about X” and “around X” are intended to teach and provide written description support for a claim limitation of, e.g., “0.98X.”
  • “about X” or “around X” indicates from (X-1) to (X+1).
  • “about X” or “around X” specifically indicates at least the values X, X-1, and X+1.
  • the present invention provides novel integrin agonist prodrugs and improved methods for treating b2 integrin-mediated conditions.
  • Compounds provided herein increase the adhesion and functional properties of b2 integrin-expressing cells, including leukocytes such as neutrophils, macrophages, and other myeloid cells, as well as microglia. Such cells can be present in the circulation or resident in tissues or tumors. Reducing recruitment of inflammatory immune cells into tissues by increasing cell adhesion allows for the treatment of acute inflammation, chronic inflammation, cancer, neurological conditions, and other diseases. Additionally, integrin activation affects various cellular functions, such as phagocytosis and signaling pathways.
  • the invention provides a compound according to Formula I: , or a pharmaceutically acceptable salt thereof, wherein: X is S or O; Y is NR 1a , S, or O; Z is O or NR 1a ; L 1 is a covalent bond, C 1-6 alkylene, 1- to 6-membered heteroalkylene, -C(O)O- (C 1-6 alkylene)-, -C(O)NR 1a -(C 1-6 alkylene)-, -(C 1-6 alkylene)-OC(O)- or -(C 1-6 alkylene)-OC(O)O-; R 1 is C 1-12 alkyl, C 2-12 alkenyl, C 3-12 cycloalkyl, 5- to 12-membered heterocycloalkyl, C 6-12 aryl, or 5- to 12-membered heteroaryl, wherein R 1 is optionally substituted with one or more of –OH, C 1-6 alkyl, hydroxy-(C 1-6 alkyl, hydroxy
  • the invention provides a compound of Formula I wherein X is O and Y is NR 1a , in which R 1a can be H, methyl, ethyl, propyl, butyl, pentyl, or hexyl.
  • R 1a can be H, methyl, ethyl, propyl, butyl, pentyl, or hexyl.
  • Y when X of a compound of Formula I is O, Y is also O.
  • when X of a compound of Formula I is O is S.
  • the invention provides a compound of Formula I wherein X is S and Y is NR 1a , wherein R 1a is as defined above.
  • when X of a compound of Formula I is S Y is O.
  • the invention provides a compound having a structure according to Formula Ia: or a pharmaceutically acceptable salt thereof, wherein: X is S or O; L 1 is a covalent bond, C 1-6 alkylene, 1- to 6-membered heteroalkylene, -C(O)O- (C 1-6 alkylene)-, -C(O)NR 1a -(C 1-6 alkylene)-, -(C 1-6 alkylene)-OC(O)- or -(C 1-6 alkylene)-OC(O)O-; R 1 is C 1-12 alkyl, C 2-12 alkenyl, C 3-12 cycloalkyl, 5- to 12-membered heterocycloalkyl, C 6-12 aryl, or 5- to 12-membered heteroaryl, wherein R 1 is optionally
  • the invention provides a compound of Formula Ia wherein L 1 is a covalent bond.
  • L 1 of a compound of Formula Ia is a C 1-6 alkylene, which can be linear or branched.
  • X in compounds of Formula Ia is S and L 1 is a covalent bond.
  • X in compounds of Formula Ia is O and L 1 is a covalent bond.
  • X in compounds of Formula Ia is S and L 1 is a C 1-6 alkylene selected from methylene (i.e., –CH 2 –), ethylene (i.e., –CH 2 CH 2 –), propylene (i.e., –C H 2 CH 2 CH 2 –), isopropylene, butylene, isobutylene, sec-butylene, pentylene and hexylene.
  • X in compounds of Formula Ia is O and L 1 is a C 1-6 alkylene selected from methylene (i.e., –CH 2 –), ethylene (i.e., – CH 2 CH 2 –), propylene (i.e., –CH 2 CH 2 CH 2 –), isopropylene, butylene, isobutylene, sec-butylene, pentylene and hexylene.
  • L 1 of a compound of Formula Ia is a linear or branched C 1-6 alkylene, which can be substituted or unsubstituted.
  • the invention provides a compound of Formula Ia wherein X is O, L 1 is a covalent bond, and R 1 is selected from C 1-6 alkyl, 5- to 8-membered heterocycloalkyl, C6-10 aryl, and 5- to 9-membered heteroaryl, wherein R 1 is optionally substituted with one or more members selected from –OH, C 1-6 alkyl, hydroxy-(C 1-6 alkyl)–, C 1-6 alkoxy, -C(O)OR 1a , -N(R 1b )m, P(O)(OR 1a ) 2 , and S(O) 2 R 1c .
  • the invention provides a compound of Formula Ia wherein X is S, L 1 is a covalent bond, and R 1 is selected from C 1-6 alkyl, 5- to 8-membered heterocycloalkyl, C6-10 aryl, and 5- to 9-membered heteroaryl, wherein R 1 is optionally substituted with one or more members selected from –OH, C 1-6 alkyl, hydroxy-(C 1-6 alkyl)–, C 1-6 alkoxy, -C(O)OR 1a , -N(R 1b ) m , P(O)(OR 1a ) 2 , and S(O) 2 R 1c .
  • the invention provides a compound of Formula Ia wherein X is O, L 1 is a C 1-6 alkylene, and R 1 is selected from C 1-6 alkyl, 5- to 8-membered heterocycloalkyl, C6-10 aryl, and 5- to 9-membered heteroaryl, wherein R 1 is optionally substituted with one or more members selected from –OH, C 1-6 alkyl, hydroxy-(C 1-6 alkyl)–, C 1-6 alkoxy, -C(O)OR 1a , -N(R 1b )m, P(O)(OR 1a ) 2 , and S(O) 2 R 1c .
  • the invention provides a compound of Formula Ia wherein X is S, L 1 is a C 1-6 alkylene, and R 1 is selected from C 1-6 alkyl, 5- to 8-membered heterocycloalkyl, C6-10 aryl, and 5- to 9-membered heteroaryl, wherein R 1 is optionally substituted with one or more members selected from – OH, C 1-6 alkyl, hydroxy-(C 1-6 alkyl)–, C 1-6 alkoxy, -C(O)OR 1a ,–N(R 1b )m, P(O)(OR 1a ) 2 , and S(O) 2 R 1c .
  • R 1 in compounds of Formula Ia is selected from C 1-6 alkyl, 5- to 6-membered heterocycloalkyl, C 6 aryl, and 5- to 6-membered heteroaryl, wherein R 1 is substituted or unsubstituted.
  • R 1 is substituted with one or more members selected from –OH, C 1-6 alkyl, hydroxy-(C 1-6 alkyl)–, C 1-6 alkoxy, -C(O)OR 1a , -N(R 1b )m, P(O)(OR 1a ) 2 , and S(O) 2 R 1c .
  • R 1 is unsubstituted.
  • X in compounds of Formula Ia O, L 1 is a covalent bond, and R 1 is a substituted or unsubstituted C 1-6 alkyl, 5- to 6-membered heterocycloalkyl, C 6 aryl, and 5- to 6-membered heteroaryl.
  • X in compounds of Formula Ia S, L 1 is a covalent bond, and R 1 is a substituted or unsubstituted C 1-6 alkyl, 5- to 6-membered heterocycloalkyl, C 6 aryl, and 5- to 6-membered heteroaryl.
  • X in compounds of Formula Ia O L 1 is a C 1-6 alkylene, and R 1 is a substituted or unsubstituted C 1-6 alkyl, 5- to 6-membered heterocycloalkyl, C 6 aryl, and 5- to 6-membered heteroaryl.
  • X in compounds of Formula Ia S L 1 is a C 1-6 alkylene, and R 1 is a substituted or unsubstituted C 1-6 alkyl, 5- to 6-membered heterocycloalkyl, C 6 aryl, and 5- to 6-membered heteroaryl.
  • subscript n in the compounds of Formula Ia is selected from 0, 1, or 2.
  • subscript n in the compounds of Formula Ia is 1 or 2, in which R 2 is independently selected from halogen, C 1-6 alkyl, and C 1-6 alkoxy.
  • R 2 in compounds of Formula Ia is a halogen.
  • R 2 selected from fluorine, chlorine, and bromine.
  • R 2 is –OCH 3 .
  • R 2 is –CH 3 .
  • each R 2 in compounds of Formula Ia is independently selected from fluorine, –OCH 3 , and –CH 3 .
  • subscript n in the compounds of Formula Ia is 0.
  • the invention provides a compound having a structure according to Formula Ib: or a pharmaceutically acceptable salt thereof, wherein: L 1 is a covalent bond, C 1-6 alkylene, 1- to 6-membered heteroalkylene, -C(O)O- (C 1-6 alkylene)-, -C(O)NR 1a -(C 1-6 alkylene)-, -(C 1-6 alkylene)-OC(O)- or -(C 1-6 alkylene)-OC(O)O-; R 1 is C 1-12 alkyl, C 2-12 alkenyl, C 3-12 cycloalkyl, 5- to 12-membered heterocycloalkyl, C 6-12 aryl, or 5- to 12-membered heteroaryl, wherein R 1 is optionally substituted with one or more of –OH, C 1-6 alkyl, hydroxy-(C 1-6 alkyl)–, C 1-6 alkoxy, -C(O)OR 1a , -
  • the invention provides a compound of Formula Ib wherein R 1 is C 1-6 alkyl.
  • R 1 of a compound of Formula Ib is a C 1-6 alkyl, which can be linear or branched.
  • R 1 of a compound of Formula Ib is a C 1-6 alkyl selected from methyl (i.e., –CH 3 ), ethyl (i.e., –CH 2 CH 3 ), propyl (i.e., – CH 2 CH 2 CH 3 ), isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, and hexyl.
  • R 1 of a compound of Formula Ib is a linear or branched C 1-6 alkyl, which is substituted or unsubstituted. In some embodiments, R 1 of a compound of Formula Ib is an unsubstituted linear or branched C 1-6 alkyl.
  • R 1 of a compound of Formula Ib is a linear or branched C 1-6 alkyl, which can be substituted with one or more members selected from –OH, C 1-3 alkyl, hydroxy-(C 1-3 alkyl)–, C 1-3 alkoxy, -C(O)OR 1a , – N(R 1b )m, P(O)(OR 1a ) 2 , and S(O) 2 R 1c .
  • L 1 of a compound of Formula Ib is a covalent bond and R 1 is unsubstituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, 2- methylbutyl, or hexyl.
  • L 1 of a compound of Formula Ib is methylene, ethylene, or propylene and R 1 is unsubstituted hexyl.
  • L 1 of a compound of Formula Ib is a covalent bond and R 1 is methyl, ethyl, propyl, isopropyl, butyl, or isobutyl, wherein R 1 is substituted with one or more –OH groups.
  • L 1 of a compound of Formula Ib is a covalent bond and R 1 is 2-hydroxyethyl, 3-hydroxypropyl, 1,3-dihydroxypropyl, 2,3-dihydroxypropyl, or 3- hydroxy-2-(hydroxymethyl)propyl.
  • L 1 of a compound of Formula Ib is a covalent bond and R 1 is methyl, ethyl, propyl, isopropyl, butyl, or isobutyl, wherein R 1 is substituted with one or more –N(R 1b )m groups, wherein R 1b and subscript m are as described previously.
  • L 1 of a compound of Formula Ib is a covalent bond and R 1 is 2-aminoethyl, 2- (methylamino)ethyl, 2-(dimethylamino)ethyl, 1-(N,N,N-trimethylamino)ethyl, 2- (ethylamino)ethyl, 2-(diethylamino)ethyl, or 2-((2-hydroxyethyl)amino)ethyl, 2-(bis(2- hydroxyethyl)amino)ethyl.
  • L 1 of a compound of Formula Ib is a covalent bond and R 1 is methyl, ethyl, propyl, isopropyl, butyl, or isobutyl, wherein R 1 is substituted with one or more C 1-3 alkoxy groups.
  • L 1 of a compound of Formula Ib is a covalent bond and R 1 is 1,3-dimethoxypropanyl, 2-methoxyethyl, or 2,3-dimethoxypropyl.
  • L 1 of a compound of Formula Ib is a covalent bond and R 1 is methyl, ethyl, propyl, isopropyl, butyl, or isobutyl, wherein R 1 is substituted with one or more P(O)(OR 1a ) 2 groups, wherein each R 1a is as described previously.
  • L 1 of a compound of Formula Ib is a covalent bond and R 1 is phosphate methyl or phosphate ethyl.
  • L 1 of a compound of Formula Ib is a covalent bond and R 1 is methyl, ethyl, propyl, isopropyl, butyl, or isobutyl, wherein R 1 is substituted with one or more S(O) 2 R 1c groups, wherein each R 1c is as described previously.
  • L 1 of a compound of Formula Ib is a covalent bond and R 1 is 2-(methylsulfonyl)ethyl or 2- (hydroxysulfonyl)ethyl.
  • the invention provides a compound of Formula Ib wherein R 1 is 5- to 6-membered heterocycloalkyl.
  • R 1 of a compound of Formula Ib is a 5- to 6-membered heterocycloalkyl, which can be substituted with one or more members selected from –OH, C 1-3 alkyl, hydroxy-(C 1-3 alkyl)–, C 1-3 alkoxy, -C(O)OR 1a , – N(R 1b ) m , P(O)(OR 1a ) 2 , and S(O) 2 R 1c .
  • R 1 of a compound of Formula Ib is an unsubstituted 5- to 6-membered heterocycloalkyl.
  • R 1 of a compound of Formula Ib is a 5- to 6-membered heterocycloalkyl selected from piperazinyl, piperidinyl, 1-methylpiperidinyl, pyrrolidinyl, 1-ethylpyrrolidinyl, 3-hydroxypyrrolidinyl, morpholinyl, 1-methylpyrrolidinyl, 4-methylpiperazinyl, 4-ethylpiperazinyl, 4-(2- hydroxyethyl)piperazinyl, 4-hydroxypiperidinyl, 3-hydroxypiperidinyl, 1,4-dioxanyl, 1,3- dioxanyl, 2,2,-dimethyl-1,3-dioxanyl, 1,3-dioxolanyl, 2,2,-dimethyl-1,3-dioxolanyl, and tetrahydrofuranyl.
  • L 1 is a covalent bond. In some embodiments, L 1 is methylene, ethylene, or propylene. [050] In some embodiments, the invention provides a compound of Formula Ib wherein R 1 is C 6 aryl. In some embodiments, R 1 of a compound of Formula Ib is a C 6 aryl which can be substituted with one or more members selected from –OH, C 1-3 alkyl, hydroxy-(C 1-3 alkyl)–, C 1-3 alkoxy, -C(O)OR 1a , –N(R 1b )m, P(O)(OR 1a ) 2 , and S(O) 2 R 1c .
  • R 1 of a compound of Formula Ib is an unsubstituted C 6 aryl.
  • R 1 of a compound of Formula Ib is a C 6 aryl selected from benzyl, 2,6-dihydroxybenzyl, 3,5- dihydroxybenzyl, 3,4-dihydroxybenzyl, 4-hydroxybenzyl, 3-hydroxybenzyl, 2- hydroxybenzyl, and benzo[d][1,3]dioxolyl.
  • L 1 is a covalent bond.
  • L 1 is methylene, ethylene, or propylene.
  • the invention provides a compound of Formula Ib wherein R 1 is 5- to 6-membered heteroaryl.
  • R 1 of a compound of Formula Ib is a 5- to 6-membered heteroaryl which can be substituted with one or more members selected from –OH, C 1-3 alkyl, hydroxy-(C 1-3 alkyl)–, C 1-3 alkoxy, -C(O)OR 1a , –N(R 1b )m, P(O)(OR 1a ) 2 , and S(O) 2 R 1c .
  • R 1 of a compound of Formula Ib is an unsubstituted 5- to 6-membered heteroaryl.
  • R 1 of a compound of Formula Ib is a 5- to 6-membered heteroaryl selected from 1H-imidazolyl, 1-methylimidazolyl, furanyl, pyridinyl, and 1H-tetrazole.
  • L 1 is a covalent bond.
  • L 1 is methylene, ethylene, or propylene.
  • R 1 in compounds of Formula Ib is selected from C 1-3 alkyl, 5- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl-, wherein R 1 is optionally substituted with one or more members selected from –OH, C 1-3 alkyl, hydroxy- (C 1-3 alkyl)–, and -N(R 1b ) m .
  • each R 1b in compounds of Formula Ib is independently selected from H and C 1-3 alkyl.
  • R 1 in compounds of Formula Ib is selected from –CH 3 , pyridinyl-(C 1-3 alkyl)–, and N(CH3) 2 -(C 1-3 alkyl)–.
  • the compound has one of the following structures:
  • the compound has one of the following structures:
  • the compound has one of the following structures:
  • Compounds of Formula I may be prepared by contacting a suitably substituted alcohol (when Z is O) or amine (when Z is NR 1a ) with a carboxylic acid starting material under standard ester bond forming reaction conditions.
  • Suitable coupling agents are known in the art and include for example, carbodiimides (e.g., N,N ⁇ - dicyclohexylcarbodiimide (DCC), N,N ⁇ -dicyclopentylcarbodiimide, N,N ⁇ - diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N-t- butyl-N-methylcarbodiimide (BMC), N-t-butyl-N-ethylcarbodiimide (BEC), 1,3-bis(2,2- dimethyl-1,3-dioxolan-4-ylmethyl)carbodiimide (BDDC), etc.), phosphonium salts (HOBt, PyBOP, HOAt, etc.), aminium/uronium salts (e.g., tetramethyl aminium salts, bispyrrolidin
  • DMAP N,N-(dimethylamino)pyridine
  • the –OH group of caboxylic acid starting material can also be converted to a leaving group, thereby forming an activated derivative, wherein activated derivatives include, but are not limited to, anhydrides (including symmetric, mixed, or cyclic anhydrides), activated esters (e.g., p-nitrophenyl esters, pentafluorophenyl esters, N-succinimidyl esters, and the like), acylazoles (e.g., acylimidazoles, preapared using carbonyl diimidazole, and the like), acyl azides, and acid halides (e.g., acid chlorides).
  • activated derivatives include, but are not limited to, anhydrides (including symmetric, mixed, or cyclic anhydrides), activated esters (e.g., p-nitrophenyl esters, pentafluorophenyl esters, N-succinimidyl esters, and the like), acylazoles
  • the invention further provides pharmaceutical compositions for the administration of the integrin agonist prodrugs described herein.
  • the pharmaceutical compositions can be prepared by any of the methods well known in the art of pharmacy and drug delivery. In general, methods of preparing the compositions include the step of bringing the active ingredient into association with a carrier containing one or more accessory ingredients.
  • the pharmaceutical compositions are typically prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the compositions can be conveniently prepared and/or packaged in unit dosage form.
  • the pharmaceutical compositions can be in the form of sterile injectable aqueous or oleaginous solutions and suspensions.
  • Sterile injectable preparations can be formulated using non-toxic parenterally-acceptable vehicles including water, Ringer’s solution, and isotonic sodium chloride solution, and acceptable solvents such as 1,3-butane diol.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Aqueous suspensions contain the active materials in admixture with excipients including, but not limited to: suspending agents such as sodium carboxymethylcellulose, methylcellulose, oleagino-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin, polyoxyethylene stearate, and polyethylene sorbitan monooleate; and preservatives such as ethyl, n-propyl, and p-hydroxybenzoate.
  • suspending agents such as sodium carboxymethylcellulose, methylcellulose, oleagino-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia
  • dispersing or wetting agents such as lecithin, polyoxyethylene stearate, and polyethylene sorbitan monooleate
  • preservatives such as ethyl,
  • Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions can contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules (suitable for preparation of an aqueous suspension by the addition of water) can contain the active ingredient in admixture with a dispersing agent, wetting agent, suspending agent, or combinations thereof. Additional excipients can also be present.
  • the pharmaceutical compositions of the invention can also be in the form of oil-in- water emulsions.
  • the oily phase can be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents can be naturally-occurring gums, such as gum acacia or gum tragacanth; naturally-occurring phospholipids, such as soy lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate; and condensation products of said partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.
  • compositions containing the integrin agonist prodrugs described herein can also be in a form suitable for oral use.
  • suitable compositions for oral administration include, but are not limited to, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, elixirs, solutions, buccal patches, oral gels, chewing gums, chewable tablets, effervescent powders, and effervescent tablets.
  • Compositions for oral administration can be formulated according to any method known to those of skill in the art.
  • compositions can contain one or more agents selected from sweetening agents, flavoring agents, coloring agents, antioxidants, and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets generally contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients, including: inert diluents, such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrating agents, such as corn starch and alginic acid; binding agents, such as polyvinylpyrrolidone (PVP), cellulose, polyethylene glycol (PEG), starch, gelatin, and acacia; and lubricating agents such as magnesium stearate, stearic acid, and talc.
  • inert diluents such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol
  • the tablets can be uncoated or coated, enterically or otherwise, by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • Tablets can also be coated with a semi-permeable membrane and optional polymeric osmogents according to known techniques to form osmotic pump compositions for controlled release.
  • compositions for oral administration can be formulated as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (such as calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium (such as peanut oil, liquid paraffin, or olive oil).
  • an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin
  • an oil medium such as peanut oil, liquid paraffin, or olive oil.
  • the integrin agonist prodrugs described herein can also be administered topically as a solution, ointment, cream, gel, suspension, mouth washes, eye-drops, and the like. Still further, transdermal delivery of the integrin agonist prodrugs can be accomplished by means of iontophoretic patches and the like.
  • the compound can also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials include cocoa butter and polyethylene glycols.
  • an integrin agonist prodrug described herein is administered via intraperitoneal injection.
  • the integrin agonist prodrug is administered orally.
  • the integrin agonist prodrug is administered intravenously.
  • the integrin agonist prodrugs described herein can be used in combination with drugs selected from, but not limited to, 5-fluorouracil, AZD8055, bevacizumab, bortezomib, cetuximab, cyclophosphamide, docetaxel, gemcitabine, imatinib, ipilimumab, lapatinib, paclitaxel, pembrolizumab, pertuzumab, rapamycin, sipuleucel-T, sorafenib, sunitinib, trastuzumab, temsirolimus, vemurafenib, taxol, paclitaxel, abiraterone, steroids, corticosteroids, prednisone, NSAIDs, mitomycin, androgens, antiandrogens, estrogens, antiestrogens, statins, CTLA-4 inhibitors, anti-CTLA-4 antibodies, B7
  • the pharmaceutical compositions of the invention can also include micronized integrin agonist.
  • Micronized integrin agonist prodrug particles generally consist essentially of the integrin agonist prodrug with average diameters below 50 ⁇ m.
  • the average diameter of the integrin agonist prodrug particles can be, for example, below 45 ⁇ m, below 40 ⁇ m, below 35 ⁇ m, below 30 ⁇ m, below 25 ⁇ m, or below 20 ⁇ m.
  • the average diameter of the integrin agonist prodrug particles can be from about 10 ⁇ m to about 49 ⁇ m, or from about 10 ⁇ m to about 45 ⁇ m, or from about 15 ⁇ m to about 40 ⁇ m, or from about 20 ⁇ m to about 35 ⁇ m, or from about 25 ⁇ m to about 30 ⁇ m.
  • the average diameter of the integrin agonist prodrug particles can be about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or about 25 ⁇ m.
  • the integrin agonist prodrugs described herein can be used for treating a disease or condition associated with the activity of b2 integrins.
  • the b2 integrin is CD11b/CD18.
  • subjects in need of treatment include subjects having a disease or condition selected from aortic aneurisms; arteritis; asthma; atherosclerosis; autoimmune diseases (including lupus, psoriasis, Crohn’s disease, multiple sclerosis, bullous pemphigoid, and rheumatoid arthritis); bowel conditions (including irritable bowel syndrome, inflammatory bowel disease, and ulcerative colitis); burn; cachexia including cardiac cachexia; cancer, including primary tumors and metastatic tumors, such as breast cancer, ovarian cancer, prostate cancer, melanoma, lung cancer, pancreatic cancer, sarcoma, tenosynovial giant cell tumor and leukemia; cardiovascular disease; Chediak-Higashi syndrome; chronic
  • the integrin agonist prodrugs can be used in conjunction with processes such as transplantation (including cell transplantation, organ transplantation, and bone marrow transplantation); organ and cell preservation; and stem cell therapies.
  • the disease or condition associated with the activity of b2 integrins is kidney disease, a condition that affects millions of people in the world and leads to renal failure.
  • the disease or condition associated with the activity of b2 integrins is restenosis. Restenosis is a frequent problem in people who have undergone angioplasty, one of the most common procedures in interventional cardiology.
  • the integrin agonist prodrugs described herein can be used for treating cancer or reducing tumors in patients.
  • the integrin agonist prodrugs modulate tumor infiltration of leukocytes.
  • Tumors secrete inflammatory cytokines to recruit cells expressing b2 integrins, such as CD11b/CD18, to facilitate neovascularization.
  • b2 integrins such as CD11b/CD18
  • tumors recruit large numbers of specific leukocytes or bone marrow-derived cells that restore tumor vasculature and allow tumor re-growth and recurrence. Therefore, the compounds and methods of this invention are useful in reducing activity, such as infiltration, of such cells.
  • activating CD11b can enhance anti-tumor immune responses.
  • integrins can modify polarization of microglia and myeloid cells, such as macrophages, thus modifying the tumor and tissue microenvironment.
  • compounds that agonize CD11b including the integrin agonist prodrugs described herein as well as other compounds, can be used to target and exploit immunomodulatory pathways for anti-tumor therapy.
  • the integrin agonist prodrugs described herein are useful in enhancing the response of other cancer treatments, such as chemotherapy, antibody therapy, radiation therapy, and cell-based therapies.
  • the integrin agonist prodrugs forms described can be used to decrease leukocyte recruitment upon injury, inflammation, bacterial infection, viral infection, or other diseases and conditions in mammals.
  • the integrin agonist prodrugs can be used to reduce organ injury, including neointimal hyperplasia upon arterial injury.
  • the integrin agonist prodrugs can be used to preserve organ function upon acute organ injury, such as ischemia-reperfusion injury.
  • the integrin agonist prodrugs can preserve kidney function upon acute kidney injury.
  • the integrin agonist prodrugs described herein can be used to preserve kidney function upon glomerular nephritis or nephrosis.
  • the integrin agonist prodrugs described herein can be used to modulate the function of inflammatory cells, such as lymphocytes and leukocytes.
  • the compounds can be used to treat integrin-mediated inflammation in a number of organs and tissues including, but not limited to, integrin-mediated inflammation of the eye, the brain, the skin, the liver, and the kidney.
  • the integrin agonist prodrugs can be used to induce graft tolerance in a recipient animal. Grafts can include bone marrow, bone marrow cells, stem cells, immune cells, engineered cells, organs, tissues or other cells.
  • the integrin agonist prodrugs can reduce graft-vs-host disease in the recipient.
  • the integrin agonist prodrugs can improve transplantation outcomes.
  • the invention provides methods for preventing or treating a b2 integrin- mediated condition or disease in a patient comprising administering to said patient a therapeutically effective amount of an integrin agonist prodrug described herein.
  • the b2 integrin-mediated condition or disease is a CD11b/CD18-mediated condition or disease.
  • the integrin agonist prodrugs described herein can be used to treat conditions related to the activity of adenosine A2A receptors and glucocorticoid receptors.
  • the integrin agonist prodrugs are used for the treatment of neurological conditions such as Alzheimer’s disease.
  • treatment of the neurological condition includes modulation of microglia cell function by the integrin agonist.
  • treatment of Alzheimer’s disease includes reduction of soluble Ab levels and Ab half-life in brain interstitial fluid (ISF) by the integrin agonist.
  • Treatment of Alzheimer’s disease can include co-administration of an integrin agonist prodrug as described herein with an A b-targeted therapy, an ApoE-targeted therapy, a tau-targeted therapy, or a combination thereof.
  • a b-targeted therapies include inhibitors of A b production (such as beta-secretase inhibitors, gamma-secretase inhibitors, alpha-secretase activators), inhibitors of A b aggregation, inhibitors of A b oligomerization, and up-regulators of A b clearance, among others (see, e.g., Jia, et al. BioMed Research International, 2014. Article ID 837157, 22 pages).
  • Examples of A b-targeted therapies include but are not limited to, antibodies, pioglitazone, begacestat, atorvastatin, simvastatin, etazolate, and tramiprosate, as well as pharmaceutically acceptable salts thereof.
  • ApoE-targeted therapies include, but are not limited to retinoid X receptor agonists (see, Cramer, et al., Science 2012.335(6075): 1503–1506) and others described by Liu et al. (Nat Rev Neurol.2013.9(2): 106–118).
  • Tau- targeted therapies include, but are not limited to, methylthioninium, leuco-methylthioninium, antibodies and those described by Lee, et al. (Cold Spring Harb Perspect Med 2011; 1:a006437).
  • the integrin agonist prodrugs are used for the treatment of inflammatory bowel diseases such as Crohn’s disease or ulcerative colitis.
  • treatment of Crohn’s disease and/or ulcerative colitis can include co- administration of an integrin agonist prodrug as described herein with an anti-inflammatory.
  • the anti-inflammatory can be an NSAID (e.g., apazone, diclofenac, ibuprofen, indomethacin, ketoprofen, nabumetone, naproxen, piroxicam, and sulindac, as well as pharmaceutically acceptable salts thereof), a TNFa inhibitor/modulator (e.g., an anti-TNFa antibody such as adalimumab), an anti-interleukin agent (e.g., an anti-IL6 receptor antibody such tocilizumab or an anti-IL5 antibody such as siltuximab), or an anti-inflammatory cytokine (e.g., recombinant IL-4, IL-10, or IL-13).
  • an NSAID e.g., apazone, diclofenac, ibuprofen
  • the invention provides a method for treating cancer.
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of an integrin agonist prodrug as described herein, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an immune checkpoint inhibitor.
  • Immuno checkpoint refers to a regulatory pathway that contributes to co- stimulatory or inhibitory control of T-cell activity in an organism. Interaction of “immune checkpoint proteins,” including proteins on the surfaces of antigen-presenting cells and T- cells, contribute to regulation and maintenance of self-tolerance and the duration and amplitude of physiological immune responses in the organism. See, e.g., D.M. Pardol. Nature Reviews Cancer 12, 252-264 (2012).
  • immune checkpoint proteins include, but are not limited to, A2aR (adenosine A2a receptor); BTLA, B, and T (lymphocyte attenuator); ICOS (inducible T cell co-stimulator); KIR (killer cell immunoglobulinlike receptor); LAG3 (lymphocyte activation gene 3); PD1 (programmed cell death protein 1); CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4); and TIM3 (T cell membrane protein 3).
  • A2aR adenosine A2a receptor
  • BTLA, B, and T lymphocyte attenuator
  • ICOS inducible T cell co-stimulator
  • KIR killer cell immunoglobulinlike receptor
  • LAG3 lymphocyte activation gene 3
  • PD1 programmeed cell death protein 1
  • CTLA-4 cytotoxic T-lymphocyte-associated antigen 4
  • TIM3 T cell membrane protein 3
  • Immune checkpoint inhibitors can, for example, include antibodies or peptide-like compounds derived from antibodies.
  • the immune checkpoint inhibitor inhibits the activity of one or more targets selected from the group consisting of CTLA-4, 4-1BB (CD137), 4-1BBL (CD137L), PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, TIM3, B7H3, B7H4, VISTA, KIR, 2B4, CD160, IDO1/IDO2 (indoleamine 2,3-dioxygenase), and CGEN-15049.
  • the immune checkpoint inhibitor is a protein that binds to one or more targets selected from the group consisting of CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, TIM3, B7H3, B7H4, VISTA, KIR, 2B4, CD160, and CGEN-15049.
  • PD1 refers to programmed cell death protein 1, also known as CD279, expressed by T-cells, B-cells, and monocytes.
  • PD-1 is a type I surface glycoprotein characterized by a V-set immunoglobulin superfamily (IgSF) domain attached to a transmembrane domain and a cytoplasmic domain containing two tyrosine-based signaling motifs.
  • PD1 binds at least two ligands: PD-L1 (expressed by cells including T-cells, B-cells, dendritic cells, macrophages, and mesenchymal stem cells) and PD-L2 (expressed by cells including dendritic cells, macrophages, and mast cells).
  • CTL-4 refers to cytotoxic T-lymphocyte-associated antigen 4, also known as CD152, which is expressed exclusively on T-cells.
  • CTLA-4 includes a single Ig-fold extracellular domain with three CDR-like loops, and binds to ligands CD80 (B7.1) and CD86 (B7.2), among others, that are differentially expressed in antigen presenting cells.
  • the immune checkpoint inhibitor is selected from the group consisting of an antibody and an antigen-binding antibody fragment.
  • the immune checkpoint inhibitor is selected from the group consisting of a CTLA-4 antibody, an OX40 antibody, a PD-L1 antibody, a PD1 antibody, and a BY55 antibody.
  • the immune checkpoint inhibitor is a CTLA-4 antibody.
  • the immune checkpoint inhibitor is a PD1 antibody.
  • the immune checkpoint inhibitor is selected from the group consisting of tremelimumab, MEDI4736, MK-3475, nivolumab, CT-011, AMP224, BMS- 936559, MPLDL3280A, MSB0010718C, and ipilimumab.
  • the cancer is associated with expression of one or more leukocyte markers in the subject.
  • Leukocyte marker refers to a biomolecule (e.g., a polypeptide) found on the cell surface of a leukocyte.
  • Leukocyte markers include, but are not limited to, T-cell antigen receptors; CD1; NK cell receptors; IDO1/2; TDO; CSF1R; VEGFR; SIRPa; cell adhesion molecules (e.g., CD2, CD58 (LFA-3), CD3, CD4, CD5, CD7, CD8); b2 integrins (e.g., LeuCAM, CD11a (LFA-1), CD11b (MAC-1 (CR3)), CD11c (CR4), CD11d, CD18, CD16 (FcR111), CD21 (CR2), CD23, CD25, CD30, CD35 (CR1)); b3 integrins (e.g., CD41, CDS1); homing receptors (e.g., CD44, Mel-14); b1 integrins (e.g., CD49a-f (VLA-1), VLA- 2, VLA-3, VLA-4); CD14; CD56; CD68; CD71; and CD163.
  • cell adhesion molecules
  • the leukocyte markers are selected from the group consisting of CD11b/CD18, IDO1/2, TDO, CSF1R, CD14, CD16, CD68, VEGFR, and SIRPa.
  • the cancer expresses one or more targets for b2 integrins.
  • the targets are selected from the group consisting of ICAM-1, VCAM-1, fibronectin, vironectin, fibrinogen, and complement fragments.
  • the cancer is selected from the group consisting of a melanoma, a sarcoma, a lymphoma, a glioma, a leukemia, pancreatic cancer, a tenosynovial giant-cell tumor, breast cancer, renal cancer, ovarian cancer, prostate cancer, colon cancer, stomach cancer, and lung cancer.
  • the cancer is a melanoma.
  • the cancer patient has also been diagnosed with an autoimmune disease (e.g., multiple sclerosis, lupus, rheumatoid arthritis, Crohn’s disease, or ulcerative colitis).
  • an autoimmune disease e.g., multiple sclerosis, lupus, rheumatoid arthritis, Crohn’s disease, or ulcerative colitis.
  • the invention provides a method for treating melanoma.
  • the method comprises administering to a subject in need thereof an integrin agonist prodrug as described herein, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a PD1 antibody.
  • the invention provides a method for treating cancer which includes administering to a subject in need thereof an integrin agonist prodrug as described herein, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an agent that targets myeloid cells.
  • Myeloid cell generally refers to any white blood cell (i.e., leukocyte) which is not a lymphocyte (e.g., not a natural killer cell, T cell, or B cell). Myeloid cells include macrophages, dendritic cells, and granulocytic cells. [098] In some embodiments, the agent that targets myeloid cells inhibits the activity of one or more targets selected from the group consisting of CSF1R, IDO1/2, TDO, CCR2, CCL2, CXCR4, JAK1/2/3/4/5, PI3Kg, integrin b1, integrin a4b1 (VLA4), VEGFR.
  • targets selected from the group consisting of CSF1R, IDO1/2, TDO, CCR2, CCL2, CXCR4, JAK1/2/3/4/5, PI3Kg, integrin b1, integrin a4b1 (VLA4), VEGFR.
  • the agent that targets myeloid cells increases the activity of SIRPa.
  • the method further comprises detecting one or more leukocyte markers in a sample obtained from the subject, thereby identifying the subject as needing the treatment.
  • the leukocyte markers are selected from the group consisting of CD11b/CD18, CD11b, CD18, CD11c, CD11d, IDO1/2, TDO, CSF1R, CD14, CD16, CD68, VEGFR, and SIRPa.
  • the marker is CD11b/CD18.
  • the method further comprises monitoring treatment efficacy by imaging tumor cells with macrophage-targeted imaging agents. In some embodiments of any on the preceding aspects, the method further comprises monitoring treatment efficacy by monitoring levels of one or more macrophage markers in the subject.
  • the invention provides a method for reducing CD11b+ leukocytes in a tumor. The method comprises administering to a subject in need thereof an integrin agonist prodrug as described herein, or a pharmaceutically acceptable salt thereof, and an effective amount of an agent selected from the group consisting of an immune checkpoint inhibitor, an agent that targets myeloid cells, and combinations thereof.
  • the CD11b+ leukocytes are myeloid cells. In some embodiments, the CD11b+ leukocytes are macrophages. In some embodiments, the CD11b+ leukocytes are neutrophils. [104] In some embodiments, the ratio of anti-tumorigenic to pro-tumorigenic macrophages in the tumor tissue is changed. [105] In some embodiments, the M1/M2 macrophage ratio or M1-like/M2-like ratio is changed in the tumor. In some such embodiments, the macrophages are polarized more toward an M1 phenotype or an M1-like anti-tumor macrophage phenotype after treatment.
  • the invention provides a method for preventing tumor metastasis in a subject having cancer.
  • the method includes administering an integrin agonist prodrug as described herein, or a pharmaceutically acceptable salt thereof, and reducing infiltration of CD11b+ leukocytes in a potential metastasis site in the subject.
  • the method for preventing tumor metastasis further includes administering an effective amount of an agent selected from the group consisting of an immune checkpoint inhibitor, an agent that targets myeloid cells, and combinations thereof.
  • the integrin agonist prodrugs described herein can be administered at any suitable dose in the methods of the invention.
  • an integrin agonist prodrug is administered at a dose ranging from about 0.1 milligrams to about 2000 milligrams per kilogram of a subject’s body weight (i.e., about 0.1-2000 mg/kg).
  • the dose of the integrin agonist prodrug can be, for example, about 0.1-1000 mg/kg, or about 1-500 mg/kg, or about 25-250 mg/kg, or about 50-100 mg/kg, or about 10-100 mg/kg.
  • the dose of the integrin agonist prodrug can be about 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950 or 2000 mg/kg.
  • the dose of the integrin agonist prodrug can be administered at a dose below about 1, below about 2, below about 3, below about 4, below about 5, below about 10, below about 15, below about 20, below about 25, below about 30, below about 35, below about 40, below about 45, below about 50, below about 55, below about 60, below about 65, below about 70, below about 75, below about 85, below about 90, below about 95, below about 100, below about 150, below about 200, below about 250, below about 300, below about 350, below about 400, below about 450, below about 500, below about 550, below about 600, below about 650, below about 700, below about 750, below about 800, below about 850, below about 900, below about 950, or below about 1000 mg/kg.
  • the integrin agonist prodrug is administered at a dose below 200 mg of compound per kg of the subject’s body weight (200 mg/kg). In some embodiments, the integrin agonist prodrug is administered at a dose below 100 mg/kg. In some embodiments, the integrin agonist prodrug is administered at a dose below 50 mg/kg. In some embodiments, the integrin agonist prodrug is administered at a dose below 20 mg/kg. [109] Immune checkpoint inhibitors can be administered at any suitable dose in the methods of the invention.
  • an antibody immune checkpoint inhibitor is administered at a dose ranging from about 0.1 milligrams to about 100 milligrams per kilogram of a subject’s body weight (i.e., about 0.1-100 mg/kg).
  • the dose of the antibody immune checkpoint inhibitor can be, for example, about 0.1-50 mg/kg, or about 1-10 mg/kg.
  • the dose of the antibody immune checkpoint inhibitor can be about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg/kg.
  • the dosages can be varied depending upon the requirements of the patient, the severity of the b2 integrin-mediated disorder or condition being treated, and the particular formulation being administered.
  • the dose administered to a patient should be sufficient to result in a beneficial therapeutic response in the patient.
  • the size of the dose will also be determined by the existence, nature, and extent of any adverse side-effects that accompany the administration of the drug in a particular patient. Determination of the proper dosage for a particular situation is within the skill of the typical practitioner.
  • the total dosage can be divided and administered in portions over a period of time suitable to treat to the integrin- mediated condition.
  • Administration of an integrin agonist prodrug described herein can be conducted for a period of time which will vary depending upon the nature of the particular the b2 integrin- mediated disorder or condition, its severity and the overall condition of the patient. Administration can be conducted, for example, hourly, every 2 hours, three hours, four hours, six hours, eight hours, or twice daily including every 12 hours, or any intervening interval thereof.
  • Administration can be conducted once daily, or once every 36 hours or 48 hours, or once every month or several months.
  • a patient can be monitored for changes in his or her condition and for alleviation of the symptoms of the b2 integrin- mediated disorder or condition.
  • the dosage of the integrin agonist prodrug can either be increased in the event the patient does not respond significantly to a particular dosage level, or the dose can be decreased if an alleviation of the symptoms of the b2 integrin-mediated disorder or condition is observed, or if the disorder or condition has been ablated, or if unacceptable side effects are seen with a particular dosage.
  • a therapeutically effective amount of an integrin agonist prodrug described herein can be administered to the subject in a treatment regimen comprising intervals of at least 1 hour, or 6 hours, or 12 hours, or 24 hours, or 36 hours, or 48 hours between dosages. Administration can be conducted at intervals of at least 72, 96, 120, 168, 192, 216, or 240 hours, or the equivalent amount of days.
  • the dosage regimen can consist of two or more different interval sets. For example, a first part of the dosage regimen can be administered to a subject multiple times daily, daily, every other day, or every third day. The dosing regimen can start with dosing the subject every other day, every third day, weekly, biweekly, or monthly.
  • the first part of the dosing regimen can be administered, for example, for up to 30 days, such as 7, 14, 21, or 30 days.
  • a subsequent second part of the dosing regimen with a different interval administration administered weekly, every 14 days, or monthly can optionally follow, continuing for 4 weeks up to two years or longer, such as 4, 6, 8, 12, 16, 26, 32, 40, 52, 63, 68, 78, or 104 weeks.
  • the dosage may be maintained or kept at lower than maximum amount. If the disorder or condition relapses, the first dosage regimen can be resumed until an improvement is seen, and the second dosing regimen can be implemented again. This cycle can be repeated multiple times as necessary.
  • an integrin agonist prodrug and an immune checkpoint inhibitor are administered in synergistic amounts; in such cases the effect of the agents when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent.
  • the synergistic effect is obtained by administering the integrin agonist prodrug and the checkpoint inhibitor at concentrations below the maximally effective concentration of the drugs when administered as single agents.
  • the synergistic amounts can depend on factors including, but not limited to, the particular integrin agonist, the particular immune checkpoint inhibitor, the condition (e.g., cancer type) being treated, and the route and frequency of administration.
  • an integrin agonist prodrug as described above is administered to the subject in an amount ranging from about 1 mg/kg to about 2000 mg/kg.
  • the immune checkpoint inhibitor is administered in a synergistic amount with the integrin agonist.
  • the integrin agonist prodrug is administered orally to the subject.
  • an integrin agonist prodrug is administered to the subject in an amount ranging from about 2 mg/kg to about 100 mg/kg.
  • the immune checkpoint inhibitor is administered in a synergistic amount with the integrin agonist.
  • the integrin agonist prodrug is administered orally to the subject.
  • the integrin agonist prodrugs described herein can modulate the release of one or more secreted factors, including but not limited to cytokines and chemokines, from leukocytes. Cytokines include pro-inflammatory cytokines (e.g., interleukin (IL)-1, tumor necrosis factor (TNF)) and anti-inflammatory cytokines (e.g., IL-4, IL-10, IL-13).
  • IL interleukin
  • TNF tumor necrosis factor
  • cytokine expression results in modulation of cytokine expression (or other soluble factor) by the integrin agonist.
  • the cytokine is selected from IL-1 b, IL-6, and IL-10.
  • the soluble factor is selected from TNF-a, interferon a (IFNa), interferon b (IFNb) and interferon (IFN)-g. Soluble factors such as cytokines are inflammatory markers and can be assayed in patient sera or patient-derived cells or tissues to assess the efficacy of a particular integrin agonist prodrug in treating a particular condition.
  • a number of diagnostic assays for cytokines such IL-1 ⁇ and TNF-a are known in the art and can be used to assess the anti- inflammatory efficacy of an integrin agonist.
  • Such methods include, but are not limited to, ELISA (enzyme-linked immune-sorbent assay) and bead array systems for capture of cytokines by resin-bound antibodies and detection by flow cytometry.
  • the invention provides a method for treating cancer, wherein the method includes: determining the expression level of one or more proteins selected from the group consisting of CD11b, CD18, IDO1, IDO2, TDO, CSF1R, CD14, CD16, CD68, VEGFR, SIRPa, ARG1, UPAR, CD114, CD11a, CD11c, CD11d, CD40, A2Ra, CD47, CD45, CD4, CD8, FOXP3, CD3, ICAM1, CD31, DESMIN, alpha-smooth muscle actin, TGFb, matrix metalloproteinases, CD64, CD32, and CD89 in the subject, and administering a therapeutically effective amount of an integrin agonist prodrug as described herein to the subject.
  • the method includes: determining the expression level of one or more proteins selected from the group consisting of CD11b, CD18, IDO1, IDO2, TDO, CSF1R, CD14, CD16, CD68, VEGFR, SIRPa, ARG1,
  • determining the expression level of the proteins includes obtaining a biospecimen (such as a biopsy) from the patient and determining the expression level of the proteins in the biospecimen.
  • the method further includes administering a therapeutically effective amount of an immune checkpoint inhibitor to the subject.
  • the method further comprises periodically determining the expression level of the protein over the course of an evaluation period, and adjusting the treatment if the expression level of the protein is observed to change over the course of the evaluation period.
  • the method includes determining that the expression level of a protein in a biospecimen, such as a biopsy, obtained from a subject is higher than the expression level of the protein in a biospecimen sample obtained from a healthy subject.
  • the method includes determining that the expression level of a protein in a biopsy sample obtained from a subject is higher than the expression level of the protein in a non-cancerous tissue sample obtained from the subject.
  • the expression level of one more proteins selected from the group consisting of CD11b, CD18, IDO1, IDO2, TDO, CSF1R, CD14, CD16, CD68, VEGFR, SIRPa, ARG1, UPAR, CD114, CD11a, CD11c, CD11d, CD45, CD4, CD8, FOXP3, CD3, ICAM1, CD31, DESMIN, alpha- smooth muscle actin, CD64, CD32, and CD89 is determined.
  • the method includes determining that the expression level of a protein in a biospecimen, such as a biopsy, obtained from a subject is lower than the expression level of the protein in a biospecimen sample obtained from a healthy subject. In some embodiments, the method includes determining that the expression level of a protein in a biopsy sample obtained from a subject is lower than the expression level of the protein in a non-cancerous tissue sample obtained from the subject.
  • the expression level of one more proteins selected from the group consisting of CD11b, CD18, IDO1, IDO2, TDO, CSF1R, CD14, CD16, CD68, VEGFR, SIRPa, ARG1, UPAR, CD114, CD11a, CD11c, CD11d, CD45, CD4, CD8, FOXP3, CD3, ICAM1, CD31, DESMIN, alpha- smooth muscle actin, CD64, CD32, and CD89 is determined.
  • the invention provides a method for treating cancer, wherein the method includes: determining the level of one or more substances selected from the group consisting of colony stimulating factor 1 (CSF1); C-reactive protein (CRP); urokinase receptor (uPAR); soluble urokinase-type plasminogen activator receptor (suPAR); Glypican- 1; CD11b; vascular endothelial growth factor (VEGF); VEGF receptor; a matrix metalloproteinase such as MMP-9 and the like; TNFa; an interleukin such as IL-6, IL-1b, IL- 10, IL-17, IL-23, and the like; TGFb; interferons including IFN-a, IFN-b, and the like; tryptophan; lysine; arginine; lactate; and a microRNA in the subject, and administering a therapeutically effective amount of integrin agonist prodrug as described herein to the subject, and administering a
  • determining the level of the substance includes obtaining a blood, plasma, urine, or saliva sample from the patient and determining the expression level of the proteins in the sample. In some such embodiments, the method further includes administering a therapeutically effective amount of an immune checkpoint inhibitor to the subject. In some such embodiments, the method further comprises periodically determining the level of the substance over the course of an evaluation period, and adjusting the treatment if the level of the substance is observed to change over the course of the evaluation period. [121] In some embodiments, the method includes determining that the level of the substance in a blood, plasma, urine, or saliva sample obtained from a subject is higher than the expression level of the protein in a similar plasma sample obtained from a healthy subject.
  • the method includes determining that the level of the substance in a blood, plasma, urine, or saliva sample obtained from a subject is lower than the level of the substance in a similar sample obtained from a healthy subject.
  • the level of one more substances selected from the group consisting of colony stimulating factor 1 (CSF1); C-reactive protein (CRP); urokinase receptor (uPAR); soluble urokinase- type plasminogen activator receptor (suPAR); Glypican-1; CD11b; vascular endothelial growth factor (VEGF); VEGF receptor; a matrix metalloproteinase such as MMP-9 and the like; TNFa; an interleukin such as IL-6, IL-1b, IL-10, IL-17, IL-23, and the like; TGFb; interferons including IFN-a, IFN-b, and the like; tryptophan; lysine; arginine; lactate; and
  • METHOD B 4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2- yl)benzoic acid was alkylated with the desired alkylating agent (i.e. R 1 –L 1 –X) in the presence of a metal carbonate base such as potassium carbonate in a polar aprotic solvent such as DMF at ambient temperature. The product was isolated by extraction. [124] For either method, the final product was purified via column chromatography on silica gel eluted with dichloromethane : methanol (49:1 to 1:1). The fractions belonging to each intermediate were collected and analyzed for purity by TLC.
  • the desired alkylating agent i.e. R 1 –L 1 –X
  • a metal carbonate base such as potassium carbonate
  • a polar aprotic solvent such as DMF
  • the reaction mixture was diluted with ethyl acetate and washed with water.
  • the sample was separated and purified using column chromatography with a silica gel column and elution with dichloromethane : methanol (49:1 to 1:1).
  • the fractions belonging to each intermediate were collected and analyzed for their purity by TLC. Pure fractions were pooled and concentrated in vacuo to provide Compound 2 in 64% yield.
  • the control compounds were propantheline bromide and mevinolin (Sigma).
  • Preparation of Compound Working Solutions 1 mM working solutions of test compound and control compound mevinolin in DMSO were prepared and 1 mM working solution of control compound propantheline in acetonitrile were prepared. Propantheline was used as positive control in the human plasma stability assays and mevinolin as the positive control in the mouse plasma stability assays.
  • Preparation of Plasma The temperature of water bath and incubator were set to 37°C.
  • the frozen plasma (stored at - 80°C) was thawed immediately in a 37°C water bath and the plasma was centrifuged at 10,000 g for 5 minutes to remove clots. The supernatant was collected into a fresh tube and the pH was of the plasma was checked. Only plasma within the range of pH 7.2 to pH 8 was used. If the pH was out of range the plasma was discarded.
  • Procedure for Stability 2.5mL of 1mM working solution was added to 497.5mL of pre-incubated human or rat plasma to reach a final concentration of 5mM. The final concentration of organic solvents was 0.5 %. The assay was performed in duplicate. The reaction samples were incubated at 37°C water bath with shaking at approximately 60 rpm.
  • the final concentration of S9 fraction and NADPH were 1mg/mL and 1mM, respectively, in each well.
  • Intestinal S9 fraction were stored at -80 °C prior to use.
  • Experimental Procedure A master solution was prepared as follows: Two separate experiments were performed as follows: a) With Cofactor (NADPH): 25mL of 10mM NADPH solution was added to the incubations. The final concentration of S9 fraction and NADPH were 1mg/mL and 1mM, respectively, in each well. b) Without Cofactor (NADPH): 25mL of ultra-pure water was added to the incubations. The final concentration of S9 fraction was 1mg/mL. The master solution was pre-warmed in a water bath at 37 °C for 10 minutes. The reaction was initiated by addition of 2.5mL of 100mM control compound or test compound solution to each master solution.
  • Verapamil was used as the positive control.
  • the final concentration of test or control compound was 1mM.
  • 25mL Aliquots were removed from the reaction solution at 0.5, 15, 30, 45 and 60 minutes. The reaction was stopped by addition of 5 volumes of cold acetonitrile with IS (100nM alprazolam, 200nM caffeine and 100nM tolbutamide). Samples were centrifuged at 3220g for 20 minutes. Aliquot of 100mL of the supernatant was mixed with 100mL ultra-pure H 2 O and then used for LC-MS/MS analysis . Data Calculation Peak areas were determined from extracted ion chromatograms. Percent parent remaining was calculated from area ratio of test compound or PC.

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Abstract

La présente invention concerne des thiazolidines, des imidazolidines, des oxazolidines polycycliques et des composés apparentés, qui sont utiles en tant que promédicaments agonistes de l'intégrine. L'invention concerne également des procédés pour le traitement de maladies à médiation par l'intégrine telles que le cancer.
PCT/US2020/052034 2019-09-23 2020-09-22 Promédicaments agonistes de l'intégrine WO2021061665A1 (fr)

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