Design, synthesis and biological evaluation of ALK5 inhibitors / 中国药科大学学报

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.