2. Academic Validation
  3. Overcoming Preclinical Safety Obstacles to Discover ( S)- N-((1,2,3,5,6,7-Hexahydro- s-indacen-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5 H-pyrazolo[5,1- b][1,3]oxazine-3-sulfonamide (GDC-2394): A Potent and Selective NLRP3 Inhibitor

Overcoming Preclinical Safety Obstacles to Discover ( S)- N-((1,2,3,5,6,7-Hexahydro- s-indacen-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5 H-pyrazolo[5,1- b][1,3]oxazine-3-sulfonamide (GDC-2394): A Potent and Selective NLRP3 Inhibitor

  • J Med Chem. 2022 Nov 10;65(21):14721-14739. doi: 10.1021/acs.jmedchem.2c01250.
Christopher McBride 1,  Lynnie Trzoss 1,  Davide Povero 1,  Milos Lazic 1,  Geza Ambrus-Aikelin 1,  Angelina Santini 1,  Rama Pranadinata 1,  Gretchen Bain 1,  Ryan Stansfield 1,  Jeffrey A Stafford 1,  James Veal 1,  Ryan Takahashi 2,  Justin Ly 2,  Shu Chen 2,  Liling Liu 2,  Marika Nespi 2,  Robert Blake 2,  Arna Katewa 2,  Tracy Kleinheinz 2,  Swathi Sujatha-Bhaskar 2,  Nandhini Ramamoorthi 2,  Jessica Sims 2,  Brent McKenzie 2,  Mark Chen 2,  Mark Ultsch 2,  Matthew Johnson 2,  Jeremy Murray 2,  Claudio Ciferri 2,  Steven T Staben 2,  Michael J Townsend 2,  Craig E Stivala 2
Affiliations

Affiliations

  • 1 Jecure Therapeutics, San Diego, California 92121, United States.
  • 2 Genentech Inc., South San Francisco, California 94080, United States.
PMID: 36279149 DOI: 10.1021/acs.jmedchem.2c01250
Abstract

Inappropriate activation of the NLRP3 inflammasome has been implicated in multiple inflammatory and autoimmune diseases. Herein, we aimed to develop novel NLRP3 inhibitors that could minimize the risk of drug-induced liver injury. Lipophilic ligand efficiency was used as a guiding metric to identify a series of 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazinesulfonylureas. A leading compound from this series was advanced into safety studies in cynomolgus monkeys, and renal toxicity, due to compound precipitation, was observed. To overcome this obstacle, we focused on improving the solubility of our compounds, specifically by introducing basic amine substituents into the scaffold. This led to the identification of GDC-2394, a potent and selective NLRP3 Inhibitor, with an in vitro and in vivo safety profile suitable for advancement into human clinical trials.

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