Ligand-based substituent-anchoring design of selective receptor-interacting protein kinase 1 necroptosis inhibitors for ulcerative colitis therapy.

Receptor-interacting protein (RIP) kinase 1 is involved in immune-mediated inflammatory diseases including ulcerative colitis (UC) by regulating necroptosis and inflammation. Our group previously identified TAK-632 (5) as an effective necroptosis inhibitor by dual-targeting RIP1 and RIP3. In this study, using ligand-based substituent-anchoring design strategy, we focused on the benzothiazole ring to obtain a series of TAK-632 analogues showing significantly improving on the anti-necroptosis activity and RIP1 selectivity over RIP3. Among them, a conformational constrained fluorine-substituted derivative (25) exhibited 333-fold selectivity for RIP1 (K d = 15 nmol/L) than RIP3 (K d > 5000 nmol/L). This compound showed highly potent activity against cell necroptosis (EC 50 = 8 nmol/L) and systemic inflammatory response syndrome (SIRS) induced by TNF- α in vivo. Especially, it was able to exhibit remarkable anti-inflammatory treatment efficacy in a DSS-induced mouse model of UC. Taken together, the highly potent, selective, orally active anti-necroptosis inhibitor represents promising candidate for clinical treatment of UC. Ligand-based substituent-anchoring design led to a C-5-F-substituted benzothiazole 25 with different conformation of TAK-632 showed high RIP1 selectivity (K d = 15 nmol/L) over RIP3 (K d > 5000 nmol/L). It exhibited significant anti-necroptosis activity and anti-inflammatory therapeutic efficacy in a DSS-induced mouse model of ulcerative colitis. [Display omitted] [ABSTRACT FROM AUTHOR]