Corbin Jackie D, Beasley Alfreda, Blount Mitsi A, Francis Sharron H
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, 702 Light Hall, Nashville, TN 37232-0615, USA.
Neurochem Int. 2004 Nov;45(6):859-63. doi: 10.1016/j.neuint.2004.03.016.
Phosphodiesterase-5 (PDE5) inhibitors act by competing with the substrate, cGMP, for the catalytic site of the enzyme. Two commercialized PDE5 inhibitors, sildenafil and vardenafil, are being used to treat erectile dysfunction. These two compounds differ in the heterocyclic ring system used to mimic the purine ring of cGMP. They also differ in the substituent (ethyl/methyl) of a piperazine side chain. Although these are the only two structural differences, vardenafil has more than 20-fold greater potency than sildenafil for inhibiting purified PDE5. The molecular structural basis for the difference in potency of the two compounds was investigated by synthesizing an analog of sildenafil ("methyl-sildenafil") that contained the sildenafil ring system but with the appended ethyl group found in vardenafil, and an analog of vardenafil ("demethyl-vardenafil") that contained the vardenafil ring system but with the appended methyl group found in sildenafil. The IC50 of methyl-sildenafil for inhibiting PDE5 indicated that it was 64 times less potent than demethyl-vardenafil, which was similar to the finding that, based on IC50, sildenafil was 40 times less potent than vardenafil. Similarly, the EC50 of methyl-sildenafil for inhibiting [3H]vardenafil binding to PDE5 indicated that it was 84 times less potent than demethyl-vardenafil, while the EC50 for sildenafil indicated that it was 31 times less potent than vardenafil. It is concluded that the methyl/ethyl appended group on the piperazine moiety plays very little role in the difference in potency between sildenafil and vardenafil for inhibiting PDE5, whereas the differences in the ring systems play a critical role in higher potency of vardenafil over sildenafil.
磷酸二酯酶-5（PDE5）抑制剂通过与底物环磷酸鸟苷（cGMP）竞争该酶的催化位点来发挥作用。两种已商业化的PDE5抑制剂，西地那非和伐地那非，正被用于治疗勃起功能障碍。这两种化合物在用于模拟cGMP嘌呤环的杂环系统上有所不同。它们在哌嗪侧链的取代基（乙基/甲基）上也存在差异。尽管这是仅有的两个结构差异，但伐地那非在抑制纯化的PDE5方面的效力比西地那非高20多倍。通过合成一种西地那非类似物（“甲基-西地那非”）来研究这两种化合物效力差异的分子结构基础，该类似物含有西地那非的环系统，但带有伐地那非中存在的附加乙基；还合成了一种伐地那非类似物（“去甲基-伐地那非”），它含有伐地那非的环系统，但带有西地那非中存在的附加甲基。甲基-西地那非抑制PDE5的半数抑制浓度（IC50）表明，其效力比去甲基-伐地那非低64倍，这与基于IC50得出的西地那非效力比伐地那非低40倍的结果相似。同样，甲基-西地那非抑制[3H]伐地那非与PDE5结合的半数有效浓度（EC50）表明，其效力比去甲基-伐地那非低84倍，而西地那非的EC50表明其效力比伐地那非低31倍。得出的结论是，哌嗪部分上的甲基/乙基附加基团在西地那非和伐地那非抑制PDE5的效力差异中作用很小，而环系统的差异在伐地那非比西地那非效力更高方面起关键作用。
