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

  • J Med Chem. 2019 Jul 25;62(14):6665-6681. doi: 10.1021/acs.jmedchem.9b00611.
Hao Zhang  1 ,  Lijuan Xu  1 ,  Xia Qin  2 ,  Xiaofei Chen  3 ,  Hui Cong  1  3 ,  Longmiao Hu  2 ,  Long Chen  3 ,  Zhenyuan Miao  3 ,  Wannian Zhang  1  3 ,  Zhenyu Cai  2  4 ,  Chunlin Zhuang  1  3  5
Affiliations
  • 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.
PMID: 31095385 DOI: 10.1021/acs.jmedchem.9b00611
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.