Compositions and methods for treating respiratory injury or disease
Inventors
Chen, Beibei • MALLAMPALLI, Rama
Assignees
University of Pittsburgh • US Department of Veterans Affairs
Publication Number
US-10092526-B2
Publication Date
2018-10-09
Expiration Date
2034-12-09
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
A method for treating a respiratory injury or disease comprising: administering to a patient in need of treatment a pharmaceutical composition comprising a compound of general Formula I:or salt, ester, solvate, hydrate, or prodrug thereof;wherein:x is an integer from 1 to 10;A and B are each, independently, C3-7cycloalkyl, C3-7cycloalkyl-C1-6alkyl, C3-7heterocycloalkyl, C3-7heterocycloalkyl-C1-6alkyl, C6-10aryl, C6-10aryl-C1-6alkyl, C3-9heteroaryl, or C3-9heteroaryl-C1-6alkyl; andn and p are each, independently, integers from 1 to 10; anda pharmaceutically acceptable carrier, excipient, or diluent.
Core Innovation
The invention provides compounds of general Formula I, including salts, esters, solvates, hydrates, or prodrugs thereof, and pharmaceutical compositions comprising these compounds for treating respiratory injuries or diseases. These compounds have specific structural features where x is an integer from 1 to 10, A and B are independently selected from various cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups optionally substituted with substituents such as halogen, alkyl, or amino derivatives. The invention also covers methods of administering these compounds in effective amounts via multiple routes to patients in need for the treatment of respiratory conditions.
The problem addressed by the invention is the secretion of pro-inflammatory cytokines following infection, injury, or irritants activating immune effector cells that underlie numerous respiratory diseases including acute and chronic bronchitis, emphysema, respiratory infections, flu, lung transplant rejection, acute lung injury, pulmonary fibrosis, asthma, cystic fibrosis, and bronchiectasis. Current approaches focus on systemic corticosteroids or targeting specific cytokines, but little is known about molecular regulation of the TNF receptor associated factors (TRAFs) at the protein stability level, which are central to inflammation signal transduction.
The invention targets the regulation of TRAF protein stability through modulation of ubiquitination pathways. Specifically, FBXO3, an ubiquitin E3 ligase subunit, mediates degradation of FBXL2 which acts as a brake on inflammation by targeting TRAF proteins for disposal. Activation of FBXO3 increases FBXL2 degradation, resulting in increased TRAFs and cytokine production, impairing lung function. The invention provides small molecule inhibitors of FBXO3 as a novel strategy to prevent or treat inflammatory respiratory diseases by modulating this pathway, thereby reducing cytokine-mediated injury.
Claims Coverage
The patent contains multiple claims directed to methods of treating respiratory injuries or diseases using pharmaceutical compositions comprising compounds of formula V. Four main inventive features are identified, focusing on the compound structure, administration routes, co-administration options, and specific substituent configurations.
Therapeutic method using compounds of formula V for respiratory injury or disease
A method of treating a respiratory injury or disease by administering to a patient in need a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt having the specified structure of formula V.
Administration routes for compounds of formula V
Administering the composition via intratracheal delivery or inhalation to treat respiratory injury or disease.
Co-administration with additional respiratory therapies
Co-administering compounds of formula V with bronchodilators, corticosteroids, or their combination.
Specific substituent configuration on compounds of formula V
Compounds where R3 and R8 are 6-membered N-heterocycles, and R1, R2, R4, R5, R6, R7, R9, and R10 are individually hydrogen or halogen, which enhances the therapeutic effect in treatment methods.
The claims focus on using pharmaceutical compositions of specific structural formula compounds to treat respiratory diseases via particular administration routes, optionally combined with other therapies, and specify particular substituents on the compounds to optimize activity.
Stated Advantages
Compounds of Formula I exhibit good anti-cytokine activity (low IC50) with relatively low toxicity (high LC50).
Compound 014 provides improved efficacy over structurally similar compounds, requiring significantly lower amounts to achieve effective inhibition of IL1β.
Use of these compounds can result in reduced side effects, lower required dosing, reduced frequency of administration, and smaller administered volumes.
The compounds effectively ameliorate lung injury and inflammation induced by pathogens like Pseudomonas aeruginosa and H1N1 influenza in animal models.
The compounds show therapeutic benefit in models of chronic lung inflammation, psoriasis, muscle myopathy, and lung transplant rejection.
Documented Applications
Treatment of respiratory injuries and diseases including acute and chronic bronchitis, emphysema, respiratory infections (pneumonia, pleurisy), flu (including influenza), post-lung transplant rejection including acute and chronic rejection and bronchiolitis obliterans, acute lung injury or the acute respiratory distress syndrome, pulmonary fibrosis, asthma, cystic fibrosis, and bronchiectasis.
Treatment of myopathy, steroid-induced myopathy, muscular dystrophy, amyotrophic lateral sclerosis (ALS), muscle weakness, critical illness myopathy, muscle atrophy, muscle wasting, rhabdomyolysis, dermatomyositis, myositis, mitochondrial myopathy, chronic obstructive lung disease, organ transplant rejection, psoriasis, myasthenia gravis, Addison's disease, celiac disease, Graves' disease, Hashimoto's thyroiditis, and pernicious anemia.
Use as a muscle building supplement to promote muscle growth.
Interested in licensing this patent?