阿伐那非生物电子等排衍生物的合成及其对磷酸二酯酶Ⅴ型抑制活性研究

傅俊杰; 雍典雅; 于水涛; 王彬; 王勇军; 胡静; 尹健

doi:10.13748/j.cnki.issn1007-7693.20243251

阿伐那非生物电子等排衍生物的合成及其对磷酸二酯酶Ⅴ型抑制活性研究

Synthesis and Study on the Phosphodiesterase Type 5 Inhibitory Activity of Bioisosteric Derivatives of Avanafil

摘要

摘要:
目的设计合成新型阿伐那非衍生物，并考察其对磷酸二酯酶Ⅴ型(phosphodiesterase type 5，PDE5)的抑制活性。
方法以阿伐那非为先导化合物，利用生物电子等排原理设计合成了20个阿伐那非衍生物，通过基于荧光偏振技术的PDE5酶活性测试，对衍生物的体外PDE5抑制活性进行定量筛选。
结果硫代酰胺衍生物Ⅰ-2、Ⅰ-4、Ⅰ-5和Ⅰ-7的PDE5抑制活性相对较好，但仍低于阿伐那非；氯代衍生物Ⅱ-1和Ⅱ-6的PDE5抑制活性较为突出，其IC₅₀值与阿伐那非相当。
结论氯代衍生物Ⅱ-1的PDE5抑制活性最好，值得进一步深入研究；构效关系分析为基于阿伐那非的PDE5抑制剂的结构优化提供了有益参考，为新型勃起功能障碍治疗药物的研发奠定了基础。

Abstract:
OBJECTIVE To design and synthesize novel avanafil derivatives and investigate their inhibitory activity on phosphodiesterase type 5(PDE5).
METHODS Using avanafil as a lead compound, 20 avanafil derivatives were designed and synthesized based on the bioisosterism principle. The in vitro inhibitory activity of these derivatives on PDE5 was quantitatively screened using a fluorescence polarization-based PDE5 enzyme activity assay.
RESULTS Among the derivatives, thioamide derivatives Ⅰ-2, Ⅰ-4,Ⅰ-5, and Ⅰ-7 demonstrated relatively good PDE5 inhibitory activity, though still lower than avanafil. The chloro derivatives Ⅱ-1 and Ⅱ-6 showed notably strong PDE5 inhibitory activity, with IC₅₀ values comparable to avanafil.
CONCLUSION Chloro derivative Ⅱ-1 exhibited the best PDE5 inhibitory activity, meriting further in-depth study. The structure-activity relationship analysis provides valuable insights for structural optimization of PDE5 inhibitors based on avanafil, laying a foundation for the development of novel erectile dysfunction therapeutics.

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