Structure-activity relationship of minoxidil analogs as inhibitors of lysyl hydroxylase in cultured fibroblasts.
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.
Murad
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Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710.
Tennant
M C
MC
Pinnell
S R
SR
D000959:Antihypertensive Agents / Q000737:chemistry* / Q000494:pharmacology; D002478:Cells, Cultured; D005347:Fibroblasts / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007223:Infant; D008297:Male; D008914:Minoxidil / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000037:antagonists & inhibitors*; D011393:Procollagen-Proline Dioxygenase / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry; D012867:Skin; D013329:Structure-Activity Relationship
D000959:Antihypertensive Agents; D010880:Piperidines; D011743:Pyrimidines; D008914:Minoxidil; C032727:piperidine; D011393:Procollagen-Proline Dioxygenase; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; C030986:pyrimidine