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

摘要: 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。

Abstract: 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.