دورية أكاديمية
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.
| العنوان: | 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. |
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| المؤلفون: | McBride C; Jecure Therapeutics, San Diego, California 92121, United States., Trzoss L; Jecure Therapeutics, San Diego, California 92121, United States., Povero D; Jecure Therapeutics, San Diego, California 92121, United States., Lazic M; Jecure Therapeutics, San Diego, California 92121, United States., Ambrus-Aikelin G; Jecure Therapeutics, San Diego, California 92121, United States., Santini A; Jecure Therapeutics, San Diego, California 92121, United States., Pranadinata R; Jecure Therapeutics, San Diego, California 92121, United States., Bain G; Jecure Therapeutics, San Diego, California 92121, United States., Stansfield R; Jecure Therapeutics, San Diego, California 92121, United States., Stafford JA; Jecure Therapeutics, San Diego, California 92121, United States., Veal J; Jecure Therapeutics, San Diego, California 92121, United States., Takahashi R; Genentech Inc., South San Francisco, California 94080, United States., Ly J; Genentech Inc., South San Francisco, California 94080, United States., Chen S; Genentech Inc., South San Francisco, California 94080, United States., Liu L; Genentech Inc., South San Francisco, California 94080, United States., Nespi M; Genentech Inc., South San Francisco, California 94080, United States., Blake R; Genentech Inc., South San Francisco, California 94080, United States., Katewa A; Genentech Inc., South San Francisco, California 94080, United States., Kleinheinz T; Genentech Inc., South San Francisco, California 94080, United States., Sujatha-Bhaskar S; Genentech Inc., South San Francisco, California 94080, United States., Ramamoorthi N; Genentech Inc., South San Francisco, California 94080, United States., Sims J; Genentech Inc., South San Francisco, California 94080, United States., McKenzie B; Genentech Inc., South San Francisco, California 94080, United States., Chen M; Genentech Inc., South San Francisco, California 94080, United States., Ultsch M; Genentech Inc., South San Francisco, California 94080, United States., Johnson M; Genentech Inc., South San Francisco, California 94080, United States., Murray J; Genentech Inc., South San Francisco, California 94080, United States., Ciferri C; Genentech Inc., South San Francisco, California 94080, United States., Staben ST; Genentech Inc., South San Francisco, California 94080, United States., Townsend MJ; Genentech Inc., South San Francisco, California 94080, United States., Stivala CE; Genentech Inc., South San Francisco, California 94080, United States. |
| المصدر: | Journal of medicinal chemistry [J Med Chem] 2022 Nov 10; Vol. 65 (21), pp. 14721-14739. Date of Electronic Publication: 2022 Oct 24. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Washington Dc : American Chemical Society Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
| مواضيع طبية MeSH: | NLR Family, Pyrin Domain-Containing 3 Protein* , Oxazines*/pharmacology , Oxazines*/therapeutic use, Animals ; Humans ; Inflammasomes ; Sulfonamides/pharmacology ; Macaca fascicularis |
| مستخلص: | 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. |
| المشرفين على المادة: | 0 (NLR Family, Pyrin Domain-Containing 3 Protein) 0 (Oxazines) 0 (Inflammasomes) 0 (Sulfonamides) |
| تواريخ الأحداث: | Date Created: 20221024 Date Completed: 20221111 Latest Revision: 20221204 |
| رمز التحديث: | 20221213 |
| DOI: | 10.1021/acs.jmedchem.2c01250 |
| PMID: | 36279149 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1520-4804 |
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| DOI: | 10.1021/acs.jmedchem.2c01250 |