Compounds to treat various lung diseases.
For how critical their function is, lung structures are surprisingly delicate, and are easily damaged by oxidants and other disease processes. Exposure to noxious agents in inspired air increases the lungs’ vulnerability, and many resultant diseases of the lungs, such as pulmonary fibrosis, acute lung injury, lung cancer, COPD, asthma, and pulmonary hypertension, have no effective current treatment, while clinicians struggle to mitigate symptoms and slow disease progression.
Technology Description
The previously-unknown compounds disclosed here demonstrate promise for treating various lung diseases. The compounds contain heteroaryl rings and two electrophilic Michael acceptors, which have been found to exhibit therapeutic properties. The Michael acceptors react readily with electron-rich compounds such as thiols and reacts with target intracellular cysteines or other targets once inside the intended cell. Because the therapeutic utility of these compounds is hindered by their limited solubility in aqueous fluids, water-soluble derivatives suitable for delivery by inhalation have been developed; direct delivery or delivery by inhalation offer the added bonuses of maximizing activity at the target organ and minimizing exposure at other tissues. These novel compounds demonstrate antioxidant and anti-inflammatory properties exerted via a mechanism distinct from that of any current pulmonary medication and have not been found to cause lung injury or extrapulmonary pathology. These compounds have produced beneficial effects in animal models of lung diseases including pulmonary fibrosis, acute lung injury, lung cancer, COPD, asthma, and pulmonary hypertension, offering exciting prospects for the future treatment of pulmonary disease.Advantages
Direct delivery reduces or eliminates potential adverse side effects
Short half-life of systemic circulation minimizes exposure to other tissue, further reducing risk to other organ systems
No extrapulmonary pathology after 30 days’ exposure with dosages 10x higher than therapeutic doses
Invention includes methods for preparing both dry powder and liquid formulations suitable for different delivery mechanisms, as well as preparation of the compound in 99% purity
Works via a mechanism distinct from any current pulmonary medication, indicating potential therapeutic benefits alone or in combination with other current treatmentsApplications
Treatment of lung diseases encompassing pulmonary fibrosis, acute lung injury, lung cancer, COPD, asthma, and pulmonary hypertensionStage of Development
In vivo dataIP Status
Reddy, Raju. Treatment of Pulmonary and Other Conditions. US 10,167,265. United States Patent and Trademark Office. Patent granted 01 Jan 2019.
Reddy, Raju. Treatment of Pulmonary and Other Conditions. US 9,862,690. United States Patent and Trademark Office. Patent granted 01 Sep 2018.
Patents issued in EP, CN, JP, IL, AU; rights pending in CA, IN, HK, GB.Innovators
Raju C. Reddy, MD
Pulmonary, Allergy, and Critical Care Medicine
Visiting Associate Professor of Medicine
Chief of Pulmonary Division, VA Pittsburgh Healthcare System
Dr. Reddy’s research interests include orphan nuclear receptors, PPARs and orphan nuclear receptors in lung disease, PPAR ligand characterization, and pulmonary drug discovery. He also works with the University of Pittsburgh’s Cystic Fibrosis Research Center.Education
Postdoctoral, National Institute of Health
Fellowship, Pulmonary and Critical Care Medicine, University of Michigan
Residency, Internal Medicine, University of Tennessee
MD, University of Tennessee
BS, Chemistry, Mathematics, Vanderbilt UniversitiesPublications
Reddy AT, Lakshmi SP, Banno A, Jadhav SK, Pulikkal Kadamberi I, Kim SC, Reddy RC. Cigarette smoke downregulates Nur77 to exacerbate inflammation in chronic obstructive pulmonary disease (COPD). PLoS One. 2020 Feb 21;15(2):e0229256. doi: 10.1371/journal.pone.0229256. eCollection 2020.
Reddy AT, Lakshmi SP, Banno A, Reddy RC. Glucocorticoid Receptor α Mediates Roflumilast's Ability to Restore Dexamethasone Sensitivity in COPD. Int J Chron Obstruct Pulmon Dis. 2020 Jan 14;15:125-134. doi: 10.2147/COPD.S230188. eCollection 2020.
Lakshmi SP, Reddy AT, Banno A, Reddy RC. Molecular, chemical, and structural characterization of prostaglandin A2 as a novel agonist for Nur77. Biochem J. 2019 Oct 15;476(19):2757-2767. doi: 10.1042/BCJ20190253.
Lakshmi SP, Reddy AT, Zhang Y, Sciurba FC, Mallampalli RK, Duncan SR, Reddy RC. Retraction: Down-regulated peroxisome proliferator-activated receptor γ (PPARγ) in lung epithelial cells promotes a PPARγ agonist-reversible proinflammatory phenotype in chronic obstructive pulmonary disease (COPD). J Biol Chem. 2019 Jan 4;294(1):69. doi: 10.1074/jbc.RX118.007042.
Banno A, Lakshmi SP, Reddy AT, Kim SC, Reddy RC. Key Functions and Therapeutic Prospects of Nur77 in Inflammation Related Lung Diseases. Am J Pathol. 2019 Mar;189(3):482-491. doi: 10.1016/j.ajpath.2018.10.002. Epub 2018 Nov 7. Review.
Reddy AT, Lakshmi SP, Banno A, Reddy RC. Identification and Molecular Characterization of Peroxisome Proliferator-Activated Receptor δ as a Novel Target for Covalent Modification by 15-Deoxy-Δ12,14-prostaglandin J2. ACS Chem Biol. 2018 Dec 21;13(12):3269-3278. doi: 10.1021/acschembio.8b00584. Epub 2018 Nov 29.