Synthesis and evaluation of 3-substituted-4-(quinoxalin-6-yl)pyrazoles as selective ALK5 inhibitors
Synthesis and evaluation of 3-substituted-4-(quinoxalin-6-yl)pyrazoles as selective ALK5 inhibitors
复制标题
选择性 ALK5 抑制剂 3-取代-4-(喹喔啉-6-基)吡唑的合成与评价
作者：
Li-Min Zhao;Zhen Guo;Yi-Jie Xue;Jun Zhe Min;Wen-Jing Zhu;Xiang-Yu Li;Hu-Ri Piao;Cheng Hua Jin
转化生长因子（transforming growth factor-，TGF-）的过度表达与多种疾病有关，已成为治疗癌症的有吸引力的分子靶点。三十二种3-取代-4-甲基喹啉衍生物，（喹喔啉-6-基）吡唑14 a-d、15 a-d、16 a-d、17 a-d、18 a-d、19 a-d、25 a、25 b、25 d、26 a、26 b、26 d、27 b、和27 d合成并评价它们的活化素TGF-I型受体激酶和p38丝裂原活化蛋白（MAP）。激酶抑制活性。在这些化合物中，最具活性的化合物19 b抑制TGF-I型受体激酶磷酸化，IC 50值为0.28 M，在10 M时抑制率为98%。化合物19 b对p38 MAP激酶也具有>35的良好选择性指数，其选择性比临床候选化合物3（LY-2157299）高9.0倍。进行分子docking.study以鉴定合成化合物的作用机制，并观察到它们良好的结合相互作用。ADMET预测结果表明，这些化合物具有良好的药动学和类药行为。
The transforming growth factor- (TGF-), in which overexpression has been associated.with various diseases, has become an attractive molecular target for the treatment of cancers..Thirty-two quinoxaline-derivatives of 3-substituted-4-(quinoxalin-6-yl) pyrazoles 14a–d, 15a–d,.16a–d, 17a–d, 18a–d, 19a–d, 25a, 25b, 25d, 26a, 26b, 26d, 27b, and 27d were synthesized and evaluated.for their activin TGF- type I receptor kinase and p38 mitogen activated protein (MAP) kinase.inhibitory activity in enzymatic assays. Among these compounds, the most active compound 19b.inhibited TGF- type I receptor kinase phosphorylation with an IC50 value of 0.28 M, with 98%.inhibition at 10 M. Compound 19b also had good selectivity index of >35 against p38 MAP kinase,.with 9.0-fold more selective than clinical candidate, compound 3 (LY-2157299). A molecular docking.study was performed to identify the mechanism of action of the synthesized compounds and their.good binding interactions were observed. ADMET prediction of good active compounds showed.that these ones possess good pharmacokinetics and drug-likeness behavior.