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J Med Chem. 2019 May 28. doi: 10.1021/acs.jmedchem.9b00611. [Epub ahead of print]

N-(7-Cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy)benzo[ d]thiazol-2-yl)cyclopropanecarboxamide (TAK-632) Analogues as Novel Necroptosis Inhibitors by Targeting Receptor-Interacting Protein Kinase 3 (RIPK3): Synthesis, Structure-Activity Relationships, and in Vivo Efficacy.

Author information

1
School of Pharmacy , Ningxia Medical University , 1160 Shengli Street , Yinchuan 750004 , China.
2
National Center for Liver Cancer , Second Military Medical University , 225 Changhai Road , Shanghai 200438 , China.
3
School of Pharmacy , Second Military Medical University , 325 Guohe Road , Shanghai 200433 , China.
4
Cancer Institute , Fudan University Shanghai Cancer Center , Shanghai 200032 , China.
5
Department of Chemistry , Fudan University , Shanghai 200433 , China.

Abstract

Necroptosis, a form of programmed cell death, plays a critical role in various diseases, including inflammatory, infectious, and degenerative diseases. We previously identified N-(7-cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy)benzo[ d]thiazol-2-yl)cyclopropanecarboxamide (TAK-632) (6) as a potent inhibitor of necroptosis by targeting both receptor-interacting protein kinase 1 (RIPK1) and 3 (RIPK3) kinases. Herein, we performed three rounds of structural optimizations of TAK-632 and elucidated structure-activity relationships to generate more potent inhibitors by targeting RIPK3. The analogues with carbamide groups exhibited great antinecroptotic activities, and compound 42 showed >60-fold selectivity for RIPK3 than RIPK1. It blocked necrosome formation by specifically inhibiting the phosphorylation of RIPK3 in necroptotic cells. In a tumor necrosis factor-induced systemic inflammatory response syndrome model, it significantly protected mice from hypothermia and death at a dose of 5 mg/kg, which was much more effective than TAK-632. Moreover, it showed favorable and druglike pharmacokinetic properties in rats with an oral bioavailability of 25.2%. Thus, these RIPK3-targeting small molecules represent promising lead structures for further development.

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