Hou, Shaohua; Yang, Xiping; Tong, Yu; Yang, Yuejing; Chen, Quanwei; Wan, Boheng; Wei, Ran; Wang, Yuchen; Zhang, Yanmin; Kong, Bo; Huang, Jianhang; Chen, Yadong; Lu, Tao; Hu, Qinghua; Du, Ding published the artcile< Structure-based discovery of 1H-indole-2-carboxamide derivatives as potent ASK1 inhibitors for potential treatment of ulcerative colitis>, Safety of 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, the main research area is triazolylpyridinyl indolecarboxamide preparation ASK1 inhibitor ulcerative colitis; structure triazolylpyridinyl indolecarboxamide inhibition ASK1; mol docking pharmacokinetics permeability triazolylpyridinyl indolecarboxamide ASK1 inhibitor; 1H-indole-2-carboxamide derivatives; ASK1 inhibitor; Ulcerative colitis.
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 a hit compound and conduct further structure-activity relationship (SAR) studies that result in the development of the indole-2-carboxamide I. I 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, I also exhibits an appropriate in vivo PK profile. In a dextran sulfate sodium (DSS)-induced mouse model of ulcerative colitis (UC), I 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, I 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.
European Journal of Medicinal Chemistry published new progress about Biological permeation. 329214-79-1 belongs to class pyridine-derivatives, and the molecular formula is C11H16BNO2, Safety of 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.