jm1c01137_si_004.pdb (188.68 kB)
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
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posted on 2022-02-03, 18:44 authored by Tao Yang, Xue Cui, Minghai Tang, Wenyan Qi, Zejiang Zhu, Mingsong Shi, Linyu Yang, Heying Pei, Wanhua Zhang, Lixin xie, Yaohui Xu, Zhuang Yang, Lijuan ChenIn
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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spirocyclic scaffolds basedshowed excellent potencyinflammatory bowel disease48 b14l b50 subsuperior derivative compoundselective dual tyk25 ] decanselective tyk2one derivativeexcellent antiinflammatory efficacyinflammatory effectth17 cellstaken togethersystematic explorationrelated tyk2regulated genesone derivativesjak inhibitorfold selectivityfindings suggestclinical candidate37 nm
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