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.

六系列的4-（苯并[ c ] [1,2,5]噻二唑-5-基）-3（5）-（6-甲基吡啶-2-基）-吡唑18a – d，19a – d，22a – d和3（5） - （6-甲基吡啶-2-基）-4-（噻吩并[3,2， - ç ] -吡啶-2-基）吡唑类20A - d，21A - d，23C，23D一直合成并评估其激活素受体样激酶5（ALK5）和p38α丝裂原活化蛋白（MAP）激酶的抑制活性。在这些化合物中，活性最高的化合物22c，在酶促测定中抑制ALK5磷酸化，IC ₅₀值为0.030μM。化合物22c显示出对ALK5激酶的有效活性是临床候选化合物LY-2157299的四倍。22c对p38αMAP激酶的选择性指数为235，远高于LY-2157299（4），并且与EW-7197（218）的选择性相同。化合物22c有效抑制了TGF-β诱导的LX-2人肝星状细胞（HSC）中胶原蛋白I和α-SMA的蛋白和mRNA表达，该结果表明化合物22c具有抑制HSC活化的能力。化合物22c 有望成为治疗肝纤维化的临床前候选药物。