ALK5抑制剂的设计、合成及其生物学活性评价

Design,synthesis and biological evaluation of ALK5 inhibitors

以ALK5抑制剂LY-3200882作为先导化合物,利用生物电子等排和构象限制等药物设计策略,结合分子对接技术,设计并合成了10个结构新颖的化合物,其结构经1H NMR、HR-MS表征。体外活性筛选结果显示,大多数化合物具有良好的激酶抑制活性。其中,化合物B4表现出显著优于LY-3200882的ALK5抑制活性(IC50=1.4 nmol/L vs 41.1 nmol/L),同时对NIH3T3细胞中TGFβ-ALK5-SMAD2/3信号通路具有良好的抑制活性(IC50=14.2 nmol/L)。进一步研究表明,化合物B4的药代动力学性质良好,口服暴露量及生物利用度满足成药性要求,值得进一步开发。

Using ALK5 inhibitor LY-3200882 as a lead compound,ten structurally novel compounds were designed by bioisosterism,conformational restriction and molecular docking technology.All structures were synthesized and confirmed by 1H NMR and HR-MS.The results of in vitro activity screening showed that most compounds had good kinase inhibitory activity.Among them,compound B4 showed significantly better ALK5 inhibitory activity than LY-3200882(IC50=1.4 nmol/L vs 41.1 nmol/L),and had good inhibitory activity against TGFβ-ALK5-SMAD2/3 signaling pathway in NIH3T3 cells(IC50=14.2 nmol/L).Besides,compound B4 had good pharmacokinetic properties,such as oral exposure and bioavailability,which is worthy of further development.