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XU Tao, WANG Xiaowei, LIU Xiaorong, WANG Yazhou, LI Zhiyu. Design, synthesis and biological evaluation of ALK5 inhibitors[J]. Journal of China Pharmaceutical University, 2020, 51(4): 441-448. DOI: 10.11665/j.issn.1000-5048.20200408
Citation: XU Tao, WANG Xiaowei, LIU Xiaorong, WANG Yazhou, LI Zhiyu. Design, synthesis and biological evaluation of ALK5 inhibitors[J]. Journal of China Pharmaceutical University, 2020, 51(4): 441-448. DOI: 10.11665/j.issn.1000-5048.20200408
shu

Design, synthesis and biological evaluation of ALK5 inhibitors

  • 1.

    School of Pharmacy, China Pharmaceutical University, Nanjing 210009

  • 2.

    Nanjing Sanhome Pharmaceutical Co. , Ltd. , Nanjing 211100，China

Funds: This study was supported by the National Science and Technology Major Project for Drug Innovation (No.2018ZX09301014-006; No.2019ZX09201001-003-005)
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  • Received Date: April 16, 2020
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    • 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.
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    • References (9)
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