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-Structure paper
タイトル | Overcoming Preclinical Safety Obstacles to Discover ()--((1,2,3,5,6,7-Hexahydro--indacen-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5-pyrazolo[5,1-][1,3]oxazine-3-sulfonamide (GDC-2394): A Potent and Selective NLRP3 Inhibitor. |
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ジャーナル・号・ページ | J Med Chem, Vol. 65, Issue 21, Page 14721-14739, Year 2022 |
掲載日 | 2022年11月10日 |
著者 | Christopher McBride / Lynnie Trzoss / Davide Povero / Milos Lazic / Geza Ambrus-Aikelin / Angelina Santini / Rama Pranadinata / Gretchen Bain / Ryan Stansfield / Jeffrey A Stafford / James Veal / Ryan Takahashi / Justin Ly / Shu Chen / Liling Liu / Marika Nespi / Robert Blake / Arna Katewa / Tracy Kleinheinz / Swathi Sujatha-Bhaskar / Nandhini Ramamoorthi / Jessica Sims / Brent McKenzie / Mark Chen / Mark Ultsch / Matthew Johnson / Jeremy Murray / Claudio Ciferri / Steven T Staben / Michael J Townsend / Craig E Stivala / |
PubMed 要旨 | 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 ...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-][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. |
リンク | J Med Chem / PubMed:36279149 |
手法 | EM (単粒子) |
解像度 | 3.5 Å |
構造データ | EMDB-28596, PDB-8etr: |
化合物 | ChemComp-MG: ChemComp-ADP: ChemComp-WTN: |
由来 |
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キーワード | HYDROLASE / NLRP3 / NACHT / inhibitor |