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-10487076-B2
Publication Date
2019-11-26
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, C1-6 alkylamino, or di-C1-6alkylamino; and n1 and p1 are each, independently, integers from 1 to 10.
Core Innovation
The invention relates to novel compounds of Formula I, II, and III, including salts, esters, solvates, hydrates, or prodrugs thereof, with specific chemical structures defined by various substituents such as alkyl, aryl, heteroaryl, and cycloalkyl groups. These compounds include benzathine based compounds that serve as FBXO3 inhibitors, and pharmaceutical compositions containing these compounds are provided for the treatment of diseases and conditions, particularly those related to inflammation and lung injury.
The problem addressed by the invention arises from the secretion of pro-inflammatory cytokines triggered by infections, host cell injury, or irritants that activate immune effector cells, leading to numerous respiratory and inflammatory diseases such as acute and chronic bronchitis, emphysema, pneumonia, flu, acute lung injury, pulmonary fibrosis, asthma, cystic fibrosis, bronchiectasis, and other inflammation related disorders. Existing therapies focus on corticosteroids or targeted anti-inflammatory agents, but there is a need for novel agents targeting the molecular regulation of inflammatory pathways.
Specifically, the invention targets the role of FBXO3, a ubiquitin E3 ligase subunit, which ubiquitinates and mediates degradation of FBXL2, a protein that regulates the TRAF family involved in cytokine release and inflammatory responses. Activation of FBXO3 leads to increased TRAF levels and cytokine production, contributing to inflammatory lung diseases. Therefore, small molecule inhibitors of FBXO3 represent a novel therapeutic strategy for prophylaxis and treatment of inflammatory diseases, by modulating cytokine release and preventing tissue damage.
Claims Coverage
The patent includes multiple independent claims directed to compounds with specific chemical structures, pharmaceutical compositions containing such compounds, and methods for treating diseases or conditions using these compounds. The main inventive features focus on novel chemical structures, their functional use as FBXO3 inhibitors, compositions, and therapeutic methods.
Compounds with defined chemical formulas and substituents
The invention claims compounds of Formulae I, II, and III, or their salts, esters, solvates, hydrates, or prodrugs, characterized by specific branched or unbranched alkyl linkers and substituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Various embodiments include options for the substituents (R1, R2, A, B, C, D, etc.) with detailed structural features, positions, and substitutions that provide the chemical diversity of the claimed compounds.
Pharmaceutical compositions containing the claimed compounds
Pharmaceutical compositions comprising the compounds of Formula I, II, or III or their salts, esters, solvates, hydrates, or prodrugs along with pharmaceutically acceptable carriers, excipients, or diluents are claimed. These compositions may include flavoring agents, lubricants, anti-inflammatory agents, antimicrobial agents, and other therapeutic agents for enhanced therapeutic effect.
Methods of treating diseases using the compounds
Methods for treating diseases or conditions comprising administering to a patient a pharmaceutical composition containing compounds of Formula I, II, or III or their derivatives in effective amounts are claimed. The methods include various administration routes such as oral, parenteral, inhalation, transdermal, and others and cover treatment of inflammatory disorders, respiratory injuries, and FBXO3-mediated disorders.
The claims cover novel chemical entities designed as FBXO3 inhibitors, pharmaceutical compositions containing these compounds, and therapeutic methods leveraging these compounds for treating inflammatory and respiratory disorders, thereby addressing the molecular mechanism of cytokine-mediated inflammation.
Stated Advantages
The compounds provide a novel strategy for selectively modulating FBXO3 activity, potentially reducing pro-inflammatory cytokine release and inflammation.
They offer an alternative to systemic corticosteroids and targeted cytokine therapies by acting at the level of protein stability and ubiquitination pathways related to TRAF proteins.
The compounds inhibit inflammation and prevent tissue damage, especially lung damage from bacterial infections or other respiratory injuries.
Documented Applications
Treatment of inflammatory disorders mediated by cytokine release including cytokine storms.
Therapeutic use in respiratory diseases such as acute and chronic bronchitis, emphysema, pneumonia, flu, post-lung transplant rejection, acute lung injury, pulmonary fibrosis, asthma, cystic fibrosis, and bronchiectasis.
Treatment of FBXO3-mediated disorders including sepsis, neuropathy, malaria, toxic lung exposure, cancer, Alzheimer’s disease, and burn-related injuries.
Use in muscle-related conditions such as myopathy, muscular dystrophy, amyotrophic lateral sclerosis, muscle weakness or wasting, and muscle building supplementation.
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