Structure-based discovery of 1H-indole-2-carboxamide derivatives as potent ASK1 inhibitors for potential treatment of ulcerative colitis

  • Eur J Med Chem. 2021 Feb 5;211:113114. doi: 10.1016/j.ejmech.2020.113114.
Shaohua Hou  1 ,  Xiping Yang  2 ,  Yu Tong  1 ,  Yuejing Yang  1 ,  Quanwei Chen  1 ,  Boheng Wan  1 ,  Ran Wei  1 ,  Yuchen Wang  1 ,  Yanmin Zhang  1 ,  Bo Kong  1 ,  Jianhang Huang  1 ,  Yadong Chen  3 ,  Tao Lu  4 ,  Qinghua Hu  5 ,  Ding Du  6
Affiliations
  • 1. School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China.
  • 2. School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China.
  • 3. School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China.
  • 4. School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China. Electronic address: [email protected].
  • 5. School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China. Electronic address: [email protected].
  • 6. School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China. Electronic address: [email protected].
PMID: 33360793 DOI: 10.1016/j.ejmech.2020.113114
Abstract

Apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein kinase (MAPK) family, is implicated in many human diseases. Here, we describe the structural optimization of hit compound 7 and conduct further structure-activity relationship (SAR) studies that result in the development of compound 19 with a novel indole-2-carboxamide hinge scaffold. Compound 19 displays potent anti-ASK1 kinase activity and stronger inhibitory effect on ASK1 in AP1-HEK293 cells than previously described ASK1 Inhibitor GS-4997. Besides improved in vitro activity, compound 19 also exhibits an appropriate in vivo PK profile. In a dextran sulfate sodium (DSS)-induced mouse model of ulcerative colitis (UC), compound 19 shows significant anti-UC efficacy and markedly attenuates DSS-induced body weight loss, colonic shortening, elevation in disease activity index (DAI) and inflammatory cell infiltration in colon tissues. Mechanistically, compound 19 represses the phosphorylation of ASK1-p38/JNK signaling pathways and suppresses the overexpression of inflammatory cytokines. Together, these findings suggest that ASK1 inhibitors can potentially be used as a therapeutic strategy for UC.

Keywords
1H-indole-2-carboxamide derivatives; ASK1 inhibitor; Ulcerative colitis.
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