Journal of medicinal chemistry · 2022
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.
СтатьяНазвание и аннотация: Перевод в очереди
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McBride Christopher, Trzoss Lynnie, Povero Davide, Lazic Milos, Ambrus-Aikelin Geza, Santini Angelina, Pranadinata Rama, Bain Gretchen, Stansfield Ryan, Stafford Jeffrey A, Veal James, Takahashi Ryan, Ly Justin, Chen Shu, Liu Liling, Nespi Marika, Blake Robert, Katewa Arna, Kleinheinz Tracy, Sujatha-Bhaskar Swathi, Ramamoorthi Nandhini, Sims Jessica, McKenzie Brent, Chen Mark, Ultsch Mark, Johnson Matthew, Murray Jeremy, Ciferri Claudio, Staben Steven T, Townsend Michael J, Stivala Craig E
Аннотация
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.