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ALK5抑制剂的设计、合成及其生物学活性评价

许涛, 王小伟, 刘晓蓉, 王亚洲, 李志裕

许涛, 王小伟, 刘晓蓉, 王亚洲, 李志裕. ALK5抑制剂的设计、合成及其生物学活性评价[J]. 中国药科大学学报, 2020, 51(4): 441-448. DOI: 10.11665/j.issn.1000-5048.20200408
引用本文: 许涛, 王小伟, 刘晓蓉, 王亚洲, 李志裕. ALK5抑制剂的设计、合成及其生物学活性评价[J]. 中国药科大学学报, 2020, 51(4): 441-448. DOI: 10.11665/j.issn.1000-5048.20200408
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

ALK5抑制剂的设计、合成及其生物学活性评价

基金项目: 国家“重大新药创制”科技重大专项资助项目(No.2018ZX09301014-006, No.2019ZX09201001-003-005)

Design, synthesis and biological evaluation of ALK5 inhibitors

Funds: This study was supported by the National Science and Technology Major Project for Drug Innovation (No.2018ZX09301014-006; No.2019ZX09201001-003-005)
  • 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.
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出版历程
  • 收稿日期:  2020-04-16
  • 刊出日期:  2020-08-24

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