Design, synthesis, and antifibrosis evaluation of 4-(benzo-[c][1,2,5]thiadiazol-5-yl)-3(5)-(6-methyl-pyridin-2-yl)pyrazole derivatives
Design, synthesis, and antifibrosis evaluation of 4-(benzo-[c][1,2,5]thiadiazol-5-yl)-3(5)-(6-methyl-pyridin-2-yl)pyrazole derivatives
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4-(苯并-[c][1,2,5]噻二唑-5-基)-3(5)-(6-甲基-吡啶-2-基)吡唑衍生物的设计、合成和抗纤维化评价
DOI：
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发表时间：
2019
影响因子：
6.7
通讯作者：
Cheng Hua Jin
中科院分区：
文献类型：
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作者：
Wen-Jing Zhu;Ben-Wen Cui;Hui Min Wang;Ji-Xing Nan;Hu-Ri Piao;Li-Hua Lian;Cheng Hua Jin
6系列4-（苯并[c][1，2，5]噻二唑-5-基）-3（5）-（6-甲基吡啶-2-基）-吡唑18 aed、19 aed、22a.ed和3（5）-（6-甲基吡啶-2-基）-4-（4-（三氟甲基）吡啶-2-基）-N-（2-（三氟甲基）吡啶-2-基）-N-（三氟甲基）-N-甲基-N-吡啶-2-基）-N-（三氟甲基）-N-甲基-N-（三氟甲基）-N-甲（噻吩并[3，2，-c]-吡啶-2-基）吡唑20 aed，21 aed，23 c，23 d.合成并在酶促测定中评价其激活素受体样激酶5（ALK 5）和p38 α促分裂原活化蛋白（MAP）激酶抑制活性。在这些化合物中，最具活性的化合物22 c在酶测定中以0.030 mM的IC 50值抑制ALK 5磷酸化。化合物22 c显示出比临床候选物化合物LY-2157299高四倍的针对ALK 5激酶的有效活性。22 c对p38 a MAP激酶的选择性指数为235，远高于LY-2157299（4），与EW-7197（218）的选择性相当。化合物22 c有效地抑制TGF-结合的LX-2人肝星状细胞（HSC）中胶原I和α-SMA的蛋白质和mRNA表达，该结果表明化合物22 c具有抑制HSC活化的能力。化合物22 c预期是治疗肝纤维化的临床前候选物。
Six series of 4-(benzo[c][1,2,5]thiadiazol-5-yl)-3(5)-(6-methylpyridin-2-yl)- pyrazoles 18aed, 19aed, 22a.ed and 3(5)-(6-methylpyridin-2-yl)-4-(thieno[3,2,-c]- pyridin-2-yl)pyrazoles 20aed, 21aed, 23c, 23d.have been synthesized and evaluated for their activin receptor-like kinase 5 (ALK5) and p38a 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 mM 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 p38a 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 a-SMA in TGF-binduced.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.