Design, synthesis and biological evaluation of ALK5 inhibitors
10.11665/j.issn.1000-5048.20200408
- VernacularTitle:ALK5抑制剂的设计、合成及共生物学活性评价
- Author:
Tao XU
1
;
Xiaowei WANG
;
Xiaorong LIU
;
Yazhou WANG
;
Zhiyu LI
Author Information
1. 中国药科大学药学院
- Publication Type:Journal Article
- Keywords:
Y-3200882;
ALK5 inhibitors;
design;
synthesis;
biological activity
- From:
Journal of China Pharmaceutical University
2020;51(4):441-448
- CountryChina
- Language:Chinese
-
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.
