European Journal of Medicinal Chemistry p. 15 - 27 (2019)
Update date:2022-08-17
Topics:
Zhu, Wen-Jing
Cui, Ben-Wen
Wang, Hui Min
Nan, Ji-Xing
Piao, Hu-Ri
Lian, Li-Hua
Jin, Cheng Hua
Six series of 4-(benzo[c][1,2,5]thiadiazol-5-yl)-3(5)-(6-methylpyridin-2-yl)- pyrazoles 18a–d, 19a–d, 22a–d and 3(5)-(6-methylpyridin-2-yl)-4-(thieno[3,2,-c]- pyridin-2-yl)pyrazoles 20a–d, 21a–d, 23c, 23d have been synthesized and evaluated for their activin receptor-like kinase 5 (ALK5) and p38α mitogen activated protein (MAP) kinase inhibitory activities in enzymatic assays. Among these compounds, the most active compound, 22c, inhibited ALK5 phosphorylation with an IC50 value of 0.030 μM in the enzymatic assay. Compound 22c showed four-fold more potent activity against ALK5 kinase than the clinical candidate, compound LY-2157299. The selectivity index of 22c against p38α MAP kinase is 235, which is much higher than that of LY-2157299 (4) and equally selective to that of EW-7197 (218). Compound 22c effectively suppressed protein and mRNA expression of collagen I and α-SMA in TGF-β-induced LX-2 human hepatic stellate cell (HSC), this result shows that compound 22c has the ability to inhibit the activation of HSC. Compound 22c is expected to be a preclinical candidate for the treatment of hepatic fibrosis.
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website:http://www.lonwinchem.com
Contact:Tel: 86-21-59858395
Address:No#966,Huaxu Road,Shanghai 201702,P.R.China
Contact:86-25-84683399
Address:605, Phoenix Herui Plaza, No.389, South Taiping Road, Nanjing, China 210002
Doi:10.1246/bcsj.40.1019
(1967)Doi:10.1021/ac504390e
(2015)Doi:10.1021/ja505037v
(2014)Doi:10.1021/acs.joc.6b01819
(2016)Doi:10.1016/j.cclet.2019.10.024
(2020)Doi:10.1021/jacs.7b08511
(2017)