2. Academic Validation
  3. Discovery and Optimization of Triazolopyrimidinone Derivatives as Selective NLRP3 Inflammasome Inhibitors

Discovery and Optimization of Triazolopyrimidinone Derivatives as Selective NLRP3 Inflammasome Inhibitors

  • ACS Med Chem Lett. 2022 Aug 1;13(8):1321-1328. doi: 10.1021/acsmedchemlett.2c00242.
David Harrison 1,  Mark G Bock 2,  John R Doedens 3,  Christopher A Gabel 3,  M Katharine Holloway 4,  Arwel Lewis 5,  Jane Scanlon 1,  Andrew Sharpe 5,  Iain D Simpson 5,  Pamela Smolak 3,  Grant Wishart 5,  Alan P Watt 1
Affiliations

Affiliations

  • 1 NodThera Ltd., Suite 8, The Mansion, Chesterford Research Park, Little Chesterford, Saffron Walden, EssexCB10 1XL, United Kingdom.
  • 2 NodThera Inc., 430 Bedford Street, Lexington, Massachusetts02420, United States.
  • 3 NodThera Inc., 454 N 34th Street, Seattle, Washington98103, United States.
  • 4 Gfree Bio LLC, 10601 Ranch Road 2222, Austin, Texas78730, United States.
  • 5 Charles River Laboratories, Chesterford Research Park, Little Chesterford, Saffron Walden, EssexCB10 1XL, United Kingdom.
PMID: 35978696 DOI: 10.1021/acsmedchemlett.2c00242
Abstract

The NLRP3 inflammasome is a multiprotein complex that facilitates activation and release of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18 in response to Infection or endogenous stimuli. It can be inappropriately activated by a range of danger signals resulting in chronic, low-grade inflammation underlying a multitude of diseases, such as Alzheimer's disease, Parkinson's disease, osteoarthritis, and gout. The discovery of potent and specific NLRP3 inhibitors could reduce the burden of several common morbidities. In this study, we identified a weakly potent triazolopyrimidone hit (1) following an in silico modeling exercise. This was optimized to furnish potent and selective small molecule NLRP3 inflammasome inhibitors. Compounds such as NDT-30805 could be useful tool molecules for a scaffold-hopping or pharmacophore generation project or used as leads toward the development of clinical candidates.

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