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-9849098-B2
Publication Date
2017-12-26
Expiration Date
2034-12-09
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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, C3-7 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; andn and p are each, independently, integers from 1 to 10; anda pharmaceutically acceptable carrier, excipient, or diluent.
Core Innovation
The invention relates to compounds of general Formula I and their pharmaceutically acceptable salts, esters, solvates, hydrates, or prodrugs, designed for treating respiratory injury or disease. These compounds have specific structural definitions where x is an integer from 1 to 10, A and B are independently selected from various cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups optionally substituted with designated substituents, and n and p are integers from 1 to 10. The compounds can be formulated into pharmaceutical compositions with carriers, excipients, or diluents, and administered via multiple routes to patients in need of treatment for respiratory ailments.
The problem addressed by the invention stems from the role of pro-inflammatory cytokines secreted after infection or injury, which activate injury pathways in respiratory diseases including bronchitis, emphysema, respiratory infections, flu, lung transplant rejection, acute lung injury, pulmonary fibrosis, asthma, cystic fibrosis, and bronchiectasis. The molecular regulation of the TRAF family at the protein stability level has remained elusive, and FBXO3, an E3 ubiquitin ligase subunit, ubiquitinates and mediates degradation of FBXL2 which acts as a brake on inflammation by targeting TRAF proteins for disposal. Increased FBXO3 activity exacerbates cytokine production and lung dysfunction in respiratory diseases, highlighting the need for novel therapeutics that selectively inhibit FBXO3 to prevent excessive inflammation.
The invention provides methods and compositions including benzathine-based compounds and analogs that inhibit FBXO3 function, thereby modulating TRAF protein concentrations to reduce cytokine release and inflammatory injury in respiratory diseases. Exemplary compounds include benzathine analogs with divalent diamine core moieties and aromatic moieties with optional N-heterocyclic substitutions. These compounds demonstrate potent anti-cytokine activity with low toxicity and improve pulmonary outcomes in various disease models including bacterial pneumonia and influenza. The invention also discloses synthetic methods to prepare these compounds and formulations suitable for diverse administration routes such as inhalation, parenteral injection, or oral delivery.
Claims Coverage
The patent includes multiple independent claims focusing on methods of treating respiratory injury or disease involving administration of pharmaceutical compositions containing specific compounds characterized by structural formulae.
Method for treating respiratory injuries or diseases with compounds of formula V
A method of treating respiratory injury or disease by administering to a patient a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt of formula V, where substitution includes N-heterocyclic groups, and with specific configurations of substituents including halogens and hydrogen atoms.
Administration routes and combination therapies
Administration of the compounds can be via intratracheal delivery, inhalation, and co-administration with bronchodilators, corticosteroids, or combinations thereof including β2 agonists, anticholinergics, and theophyllines.
Treatment of muscle-related conditions and broader disease applications
Methods include administering the compounds for muscle building and treatment of injuries, diseases, or conditions beyond respiratory diseases, highlighting versatility in therapeutic applications.
Pharmaceutical compositions with compound of formula V
Compositions comprising compounds of formula V together with pharmaceutically acceptable carriers, excipients, or diluents suitable for administration in treating respiratory conditions.
The independent claims cover the use of compounds of structural formula V and their pharmaceutically acceptable salts for treating respiratory diseases and muscle conditions, emphasizing particular structural features, administration methods including inhalation and intratracheal delivery, and combination with other therapies such as bronchodilators and corticosteroids, thereby defining a broad therapeutic scope.
Stated Advantages
Compounds of Formula I exhibit good anti-cytokine activity with relatively low toxicity, offering effective inflammation inhibition with reduced side effects.
Compound 014 provides improved efficacy compared to structurally similar compounds, enabling lower dosing to achieve therapeutic effectiveness.
Treatment with the compounds ameliorates lung mechanics parameters such as resistance, elastance, and compliance in respiratory disease models.
The compounds reduce lavage protein, cell counts, and pro-inflammatory cytokines in lung inflammation models, indicating reduced inflammatory injury.
The compounds effectively ameliorate pathological features such as neutrophil infiltration and tissue damage in lung and skin disease models, demonstrating broad anti-inflammatory activity.
Documented Applications
Treatment of respiratory injuries and diseases including acute and chronic bronchitis, emphysema, respiratory infections such as pneumonia and pleurisy, influenza, post-lung transplant rejection, acute lung injury or acute respiratory distress syndrome, pulmonary fibrosis, asthma, cystic fibrosis, and bronchiectasis.
Treatment of muscle-related conditions including myopathy, steroid-induced myopathy, muscular dystrophy, amyotrophic lateral sclerosis, muscle weakness, critical illness myopathy, muscle atrophy and 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 administered to subjects.
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