Discovery of benzoheterocyclic-substituted amide derivatives as apoptosis signal-regulating kinase 1 (ASK1) inhibitors

Lin Tang; Minxiong Li; Changlin Bai; Xuejin Feng; Haiyang Hu; Yufen Yao; Baiqing Li; Hongwei Li; Guohong Qin; Ning Xi; Genpin Lv; Lei Zhang

doi:10.1039/D3MD00663H

Discovery of benzoheterocyclic-substituted amide derivatives as apoptosis signal-regulating kinase 1 (ASK1) inhibitors†

Lin Tang,

^abc Minxiong Li,^b Changlin Bai,^b Xuejin Feng,^b Haiyang Hu,^b Yufen Yao,^d Baiqing Li,^e Hongwei Li,^f Guohong Qin,^f Ning Xi,*^g Genpin Lv*^c and Lei Zhang

*^a

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* Corresponding authors

^a MOE International Joint Research Laboratory on Synthetic Biology and Medicines, School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, P.R. China
E-mail: lzhangce@scut.edu.cn

^b Sunshine Lake Pharmaceutical Co., Ltd., Dongguan 523871, P.R. China

^c Shaoguan HEC Technology R & D Co., Ltd, Shaoguan 512000, P.R. China
E-mail: dyglee@163.com

^d Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, 510006 Guangzhou, P.R. China

^e Guangzhou National Laboratory, Guangzhou 510005, P.R. China

^f Guangdong Yuchuang Electronics Co., Ltd., Shaoguan 512721, P.R. China

^g Institute of Drug Discovery Technology, Ningbo University, Ningbo 315211, P.R. China
E-mail: xining@nbu.edu.cn

Abstract

Three series of benzoheterocyclic-substituted amide derivatives were designed and synthesized as potent ASK1 inhibitors in this work. After undergoing continuous structural optimization, compound 17a was discovered to be a novel inhibitor of ASK1 with good potency (kinase, IC₅₀ = 26 nM), noteworthy liver microsomal stability (human, T_1/2 = 340.4 min), good pharmacokinetic parameters (rat, T_1/2 p.o. = 2.11 h, AUC_last p.o. = 10 900 h ng mL⁻¹) and high oral bioavailability (rat, F = 97.9%), while also being inactive towards hERG (IC₅₀ > 10 μM).

RSC Medicinal Chemistry

Discovery of benzoheterocyclic-substituted amide derivatives as apoptosis signal-regulating kinase 1 (ASK1) inhibitors†

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Discovery of benzoheterocyclic-substituted amide derivatives as apoptosis signal-regulating kinase 1 (ASK1) inhibitors

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