Kim Dae-Kee, Young Lee Ju, Park Hyun-Ju, Minh Thai Khac
College of Pharmacy, Ewha Womans University, 11-1 Daehyun-dong, Seodaemun-gu, Seoul 120-750, South Korea.
Bioorg Med Chem Lett. 2004 May 3;14(9):2099-103. doi: 10.1016/j.bmcl.2004.02.040.
Synthesis of new sildenafil analogues containing a phosphonate group in the 5(')-sulfonamide moiety of the phenyl ring, 12a-e, 13a-d, and 14a-d, and evaluation of their in vitro PDE5 inhibitory activity are disclosed. Enzyme assays revealed that maximum 10-fold increase in PDE5 inhibitory activity, compared with sildenafil, was achieved by introducing a phosphonate group in the 5(')-sulfonamide moiety. Docking model of (PDE5: 12d) complex shows that the PDE5-bound conformation of 12d matches completely with that of sildenafil, while 12d is partially overlapped with cGMP with ethyl phosphonate group of 12d superimposed onto the cyclic phosphate group of cGMP.
公开了在苯环的5(')-磺酰胺部分含有膦酸酯基团的新型西地那非类似物12a - e、13a - d和14a - d的合成及其体外PDE5抑制活性的评估。酶分析表明，通过在5(')-磺酰胺部分引入膦酸酯基团，与西地那非相比，PDE5抑制活性最大提高了10倍。(PDE5: 12d)复合物的对接模型表明，12d与PDE5结合的构象与西地那非完全匹配，而12d与cGMP部分重叠，12d的乙基膦酸酯基团叠加在cGMP的环磷酸基团上。
