Compositions and methods for treating diseases and conditions
Inventors
Chen, Beibei • Mallampalli, Rama K.
Assignees
University of Pittsburgh • US Department of Veterans Affairs
Publication Number
US-11072606-B2
Publication Date
2021-07-27
Expiration Date
2035-12-10
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Abstract
A compound of Formula II, or a salt, ester, solvate, hydrate or prodrug thereof: where: X1 is a branched or unbranched C1-10 alkyl, (CH2)s—NH—(CH2)t, (CH2)s—O—(CH2)t, or (CH2)s—C(NH2)—(CH2)v—NH—(CH2)t, where s, t and v are each, independently an integer from 1 to 5;A and B are each, independently, C6-10aryl, C6-10aryl-C1-6alkyl, C3-9 heteroaryl, or C3-9heteroaryl-C1-6alkyl, each optionally substituted with 1, 2 or 3 independently selected Rg groups;C and D are each, independently, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-6alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl-C1-6 alkyl, C6-10aryl, C6-10aryl-C1-6alkyl, C3-9 heteroaryl, or C3-9heteroaryl-C1-6alkyl, each optionally substituted with 1, 2 or 3 independently selected Rg groups;each Rg is, independently, halogen, C1-6 alkyl, C1-6 haloalkyl, hydroxyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6alkylamino, or di-C1-6alkylamino; andn1 and p1 are each, independently, integers from 1 to 10.
Core Innovation
The invention relates to compounds of Formula II, or salts, esters, solvates, hydrates, or prodrugs thereof, characterized by specific chemical structures defined by variables including X1, A, B, C, D, Rg, n1, and p1. These compounds serve as FBXO3 inhibitors designed to modulate inflammation by targeting the ubiquitin-mediated degradation pathways involving TRAF proteins, critical in cytokine release and inflammatory responses.
The problem addressed stems from the secretion of pro-inflammatory cytokines following infections or injuries, which underlies various diseases including respiratory diseases and inflammatory disorders. Current treatments like corticosteroids or targeted agents to individual cytokines have limitations. The patent identifies a need for novel therapeutics that modulate the TRAF protein levels by inhibiting FBXO3, thereby reducing cytokine-mediated inflammation and tissue injury.
Claims Coverage
The claims cover methods of treating inflammatory disorders by administering compounds with defined chemical structures characterized by specific substituents and configurations. Two main independent claims focus on the treatment method and the chemical identity of the compounds.
Method for treating an inflammatory disorder using compounds of specified chemical formula
A method for treating an inflammatory disorder comprising administering to a subject in need a compound of Formula II with defined substituents (X1, A, B, C, D, Rg, n1, p1) where R groups can be halogen, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, amino, alkylamino, or dialkylamino, and X1 is a branched or unbranched alkyl or specific diamine/ether linkers.
Specific embodiments of compounds for diminishing cytokine levels
Compounds wherein particular substituents such as R21 and R23, or R25 and R30, or R26 and R29 are fluorine, and where X1 is a specific alkyl or —CH2CH2— linkage. These compounds are administered to diminish supraphysiological levels of TNFα, IL-β, and IL-6.
Application of compounds in treating specific inflammatory disorders
Use of the compounds to treat inflammatory bowel disease, Crohn's disease, colitis, and other inflammatory disorders including hayfever, lupus erythematosis (SLE), polymyalgia rheumatica, scleroderma, Wegener's granulomatosis, temporal arteritis, vasculitis, cryoglobulinemia, and multiple sclerosis.
The claims focus on methods of treating inflammatory disorders by administering compounds defined by precise chemical formulas that act as FBXO3 inhibitors to modulate cytokine levels and treat various inflammatory diseases including bowel diseases and systemic inflammatory conditions.
Stated Advantages
The compounds inhibit the release of pro-inflammatory cytokines such as TNFα, IL-β, and IL-6, providing broad anti-inflammatory activity.
The compounds offer a novel strategy targeting FBXO3 to prevent tissue damage including lung damage from bacterial infection and reduce hypercytokinemia.
Potential therapeutic use in a wide spectrum of inflammatory disorders, respiratory diseases, sepsis, pneumonia, cancer, and injuries linked to FBXO3-mediated pathways.
Documented Applications
Treatment of inflammatory disorders characterized by cytokine storms, including asthma, chronic obstructive lung disease, pulmonary fibrosis, pneumonia, cystic fibrosis, psoriasis, rheumatoid arthritis, colitis, lupus, multiple sclerosis, and sepsis.
Treatment of respiratory diseases and lung injuries such as acute and chronic bronchitis, emphysema, influenza, post-lung transplant rejection, acute respiratory distress syndrome, asthma, cystic fibrosis, and bronchiectasis.
Treatment of FBXO3-mediated disorders including malaria, toxic lung exposure, various cancers (including leukemia, lymphoma, carcinoma, melanoma, sarcoma, metastatic cancer), Alzheimer's, and burn-related injury.
Use as an anti-inflammatory agent to reduce cytokine-mediated inflammation and tissue damage induced by infections with pathogens like Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenza, and Escherichia coli.
Administration as pharmaceutical compositions via oral, parenteral, inhalation, transdermal, intranasal, intratracheal or other routes for treating inflammation and associated diseases.
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