FBXO3 inhibitors
AssigneesUniversity of Pittsburgh—Of the Commonwealth System of Higher Education, The United States Government as represented by the Department of Veterans Affairs
InventorsBeibei Chen, Rama K. Mallampalli
Life of this patent
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Abstract
A compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of: wherein X is a divalent linking moiety; and R1-R10 are each individually H, optionally-substituted alkyl, optionally-substituted alkoxy, optionally-substituted aryl, optionally-substituted cycloalkyl, optionally-substituted heterocyclic, halogen, amino, or hydroxy, provided that at least one of R3 or R8 is an optionally-substituted alkyl, a substituted alkoxy, optionally-substituted aryl, optionally-substituted cycloalkyl, optionally-substituted heterocyclic, or halogen.
Claims37
A method for inhibiting pro-inflammatory cytokine release in a subject in need thereof, comprising administering to the subject an FBXO3 inhibitor, wherein the FBXO3 inhibitor is an N-heterocyclic-substituted benzathine wherein the N-heterocyclic substituent is selected from pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, isoxazolyl, furazanyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, thiadiazolyl, dithiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or triazinyl.
A method for treating an inflammatory disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an FBXO3 inhibitor, wherein the FBXO3 inhibitor is an N-heterocyclic-substituted benzathine wherein the N-heterocyclic substituent is selected from pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, isoxazolyl, furazanyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, thiadiazolyl, dithiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or triazinyl, and wherein the inflammatory disorder is asthma, chronic obstructive lung disease, pulmonary fibrosis, pneumonitis, pneumonia, cystic fibrosis, psoriasis, arthritis/rheumatoid arthritis, rhinitis, pharyngitis, cystitis, prostatitis, dermatitis, allergy, nephritis, conjunctivitis, encephalitis, meningitis, opthalmitis, uveitis, pleuritis, pericarditis, myocarditis, atherosclerosis, human immunodeficiency virus related inflammation, diabetes, osteoarthritis, psoriatic arthritis, inflammatory bowel disease, colitis, sepsis, vasculitis, bursitis, connective tissue disease, autoimmune disease, viral or influenza-induced inflammation, or edema.
A method for treating an FBXO3-mediated disorder or injury in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an FBXO3 inhibitor, wherein the FBXO3-mediated disorder or injury is selected from malaria, toxic lung exposure, cancer, Alzheimer's, or a burn-related injury, wherein the cancer is selected from leukemia, lymphoma, bronchogenic carcinoma, adenocarcinoma of the breast, colon, ovary, thyroid, pancreas, stomach, or prostate, squamous cell cancer, small cell cancer, melanoma, sarcoma, or metastatic cancer, and wherein the FBXO3 inhibitor is an N-heterocyclic-substituted benzathine wherein the N-heterocyclic substituent is selected from pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, isoxazolyl, furazanyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, thiadiazolyl, dithiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or triazinyl.
A method for inhibiting FBXO3-induced ubiquitination and degradation of FBXL2 in a subject in need thereof, comprising contacting FBXO3-containing tissue or cells with an N-heterocyclic-substituted benzathine wherein the N-heterocyclic substituent is selected from pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, isoxazolyl, furazanyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, thiadiazolyl, dithiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or triazinyl.
A method for inhibiting bacterial growth in a subject in need thereof or on a surface of an object, comprising administering to the subject or the surface of the object an effective amount of an FBXO3 inhibitor.
A method for inhibiting a bioactivity of FBXO3 protein in a subject in need thereof, comprising contacting FBXO3 with a compound that interacts with amino acid residues Y308, N335, E341, T368 and 5370 that are present in an ApaG domain cavity of the FBXO3 protein.
A method for diminishing supraphysiological levels of at least one of TNFα, IL-β, or IL-6 in a subject in need thereof, comprising administering to the subject, an effective amount of a compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of formula I:
- wherein X is an alkanediyl having a structure of —CnH2n— wherein n is 2 to 5;
- R1, R2, R4-R7, R9 and R10 are each individually H, optionally-substituted alkyl, optionally-substituted alkoxy, optionally-substituted aryl, optionally-substituted cycloalkyl, optionally-substituted heterocycle, halogen, amino, or hydroxy;
- R3 is an N-heterocyclic selected from pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, isoxazolyl, furazanyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, thiadiazolyl, dithiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or triazinyl;
- and
- R8 is an N-heterocyclic selected from pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, isoxazolyl, furazanyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, thiadiazolyl, dithiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or triazinyl.
Dependencies are inferred from the claim text.