Identification of a novel orally bioavailable NLRP3 inflammasome inhibitor. Issue 21 (1st November 2020)

• Record Type: Journal Article
• Authors: Agarwal, Sameer; Pethani, Jignesh P.; Shah, Hardik A.; Vyas, Vismit; Sasane, Santosh; Bhavsar, Harsh; Bandyopadhyay, Debdutta; Giri, Poonam; Viswanathan, Kasinath; Jain, Mukul R.; Sharma, Rajiv
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 21(2020)
• Publication Date: 2020-11-01
• Subjects: NLRP3 NOD-like receptor family, pyrin domain-containing protein 3 -- AIM2 absent in melanoma 2 -- DAMP damage‐associated molecular pattern -- PAMP pathogen‐associated molecular pattern -- LPS Lipopolysaccharide -- ATP adenosinetriphosphate -- NCE new chemical entity -- LDA lithium diisopropylamide -- TFA trifluoroacetic acid -- tPSA total polar surface area -- PK pharmacokinetic; NLRP3 -- NLRP3 inflammasome -- Interleukin-1β (IL-1β) -- Inflammation -- Sulfonylurea -- Coronavirus disease 2019 (COVID-19) -- Acute respiratory distress syndrome (ARDS); Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127571
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: NLRP3 inflammasome mediated release of interleukin-1β (IL-1β) has been implicated in various diseases, including COVID-19. In this study, rationally designed alkenyl sulfonylurea derivatives were identified as novel, potent and orally bioavailable NLRP3 inhibitors. Compound 7 was found to be potent (IL-1β IC50 = 35 nM; IL-18 IC50 = 33 nM) and selective NLRP3 inflammasome inhibitor with excellent pharmacokinetic profile having oral bioavailability of 99% in mice.