Details

Autor(en) / Beteiligte

• Zhu, Wen-Jing
• Cui, Ben-Wen
• Wang, Hui Min
• Nan, Ji-Xing
• Piao, Hu-Ri
• Lian, Li-Hua
• Jin, Cheng Hua

Titel

Design, synthesis, and antifibrosis evaluation of 4-(benzo-[c][1,2,5]thiadiazol-5-yl)-3(5)-(6-methyl- pyridin-2-yl)pyrazole and 3(5)-(6-methylpyridin- 2-yl)-4-(thieno-[3,2,-c]pyridin-2-yl)pyrazole derivatives

Ist Teil von

• European journal of medicinal chemistry, 2019-10, Vol.180, p.15-27

Ort / Verlag

France: Elsevier Masson SAS

Erscheinungsjahr

2019

Quelle

Access via ScienceDirect (Elsevier)

Beschreibungen/Notizen

• 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. [Display omitted] •Six series of new pyrazole derivatives were designed and synthesized.•The most potent compound 22c showed 4.0-fold more potent activity than the clinical candidate (LY-2157299).•Compound 22c effectively inhibited TGF-β induced HSC activation.•Molecular docking study was performed into ALK5 kinase binding site.