1. Academic Validation
  2. Identification of a Novel 2,8-Diazaspiro[4.5]decan-1-one Derivative as a Potent and Selective Dual TYK2/JAK1 Inhibitor for the Treatment of Inflammatory Bowel Disease

Identification of a Novel 2,8-Diazaspiro[4.5]decan-1-one Derivative as a Potent and Selective Dual TYK2/JAK1 Inhibitor for the Treatment of Inflammatory Bowel Disease

  • J Med Chem. 2022 Feb 24;65(4):3151-3172. doi: 10.1021/acs.jmedchem.1c01137.
Tao Yang 1 Xue Cui 1 Minghai Tang 1 Wenyan Qi 1 Zejiang Zhu 1 Mingsong Shi 1 Linyu Yang 1 Heying Pei 1 Wanhua Zhang 2 Lixin Xie 1 Yaohui Xu 1 Zhuang Yang 1 3 Lijuan Chen 1 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China.
  • 2 Department of Hematology, West China Hospital of Sichuan University, Chengdu 610041, China.
  • 3 Chengdu Zenitar Biomedical Technology Co., Ltd., Chengdu 610041, China.
Abstract

In this study, we described a series of 2,8-diazaspiro[4.5]decan-1-one derivatives as selective Tyk2/JAK1 inhibitors. Systematic exploration of the structure-activity relationship through the introduction of spirocyclic scaffolds based on the reported selective Tyk2 Inhibitor 14l led to the discovery of the superior derivative compound 48. Compound 48 showed excellent potency on Tyk2/JAK1 kinases with IC50 values of 6 and 37 nM, respectively, and exhibited more than 23-fold selectivity for JAK2. Compound 48 also demonstrated excellent metabolic stability and more potent anti-inflammatory efficacy than tofacitinib in acute ulcerative colitis models. Moreover, the excellent anti-inflammatory effect of compound 48 was mediated by regulating the expression of related Tyk2/JAK1-regulated genes, as well as the formation of Th1, Th2, and Th17 cells. Taken together, these findings suggest that compound 48 is a selective dual Tyk2/JAK Inhibitor, deserving to be developed as a clinical candidate.

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