Murad S, Tennant M C, Pinnell S R
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710.
Arch Biochem Biophys. 1992 Jan;292(1):234-8. doi: 10.1016/0003-9861(92)90073-6.
The structural features that confer upon minoxidil the ability to suppress lysyl hydroxylase activity in human skin fibroblasts were investigated. Substitution of the amino group in position 2 or 6 of the pyrimidine ring with a methyl group had no significant effect on the inhibitory activity of minoxidil, whereas substitution of both amino groups with methyl groups resulted in a complete loss of inhibitory activity. Together, these observations indicate that only one of the two amino groups ortho to the nitroxide oxygen is essential for the enzyme-suppressing effect of minoxidil. Derivatives of minoxidil formed by hydroxylation at position 3 or 4 of the piperidine ring were as active as the parent compound in suppressing lysyl hydroxylase activity. However, replacement of the piperidinyl group in position 4 of the pyrimidine ring with a pyrrolidinyl, morpholinyl, or N-methylpiperazinyl group resulted in loss of inhibitory activity, demonstrating that the piperidinyl group para to the nitroxide oxygen is essential for the enzyme-suppressing effect of minoxidil. Removing the nitroxide oxygen from position 1 of the pyrimidine ring resulted in a partial loss of the specificity of minoxidil for suppression of lysyl hydroxylase activity. The results indicate that distinct structural elements determine the enzyme-suppressing effect and the antihypertensive effect of minoxidil.
研究了赋予米诺地尔抑制人皮肤成纤维细胞中赖氨酰羟化酶活性能力的结构特征。嘧啶环2位或6位的氨基被甲基取代对米诺地尔的抑制活性没有显著影响，而两个氨基都被甲基取代则导致抑制活性完全丧失。这些观察结果共同表明，对于米诺地尔的酶抑制作用而言，与硝基氧邻位的两个氨基中只有一个是必需的。哌啶环3位或4位羟基化形成的米诺地尔衍生物在抑制赖氨酰羟化酶活性方面与母体化合物活性相同。然而，嘧啶环4位的哌啶基被吡咯烷基、吗啉基或N-甲基哌嗪基取代导致抑制活性丧失，表明与硝基氧对位的哌啶基对于米诺地尔的酶抑制作用是必需的。从嘧啶环1位去除硝基氧导致米诺地尔抑制赖氨酰羟化酶活性的特异性部分丧失。结果表明，不同的结构元件决定了米诺地尔的酶抑制作用和降压作用。
