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-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (GDC-2394): A Potent and Selective NLRP3 Inhibitor

作者：Christopher McBride, Lynnie Trzoss, Davide Povero, Miloš Lazić, Geza Ambrus-Aikelin, Angelina M. Santini, Rama F. Pranadinata, Gretchen Bain, Ryan K. Stansfield, Jeffrey A. Stafford, James M. Veal, Ryan Takahashi, Justin Q. Ly, Shu Chen, Liling Liu, Marika Nespi, Robert W. Blake, Arna Katewa, Tracy Kleinheinz, Swathi Sujatha-Bhaskar, Nandhini Ramamoorthi, Jessica K. Sims, Brent S. McKenzie, Mark Chen, Mark H. Ultsch, Matthew Camp Johnson, Jeremy M. Murray, Claudio Ciferri, Steven T. Staben, Michael J. Townsend, Craig E. Stivala · 发表于：Journal of Medicinal Chemistry · 年份：2022 · DOI：10.1021/acs.jmedchem.2c01250 · 被引用次数：75 · 研究领域：Inflammasome and immune disorders、Drug-Induced Hepatotoxicity and Protection、Gout, Hyperuricemia, Uric Acid

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.