title: Structure-activity relationship of minoxidil analogs as inhibitors of lysyl hydroxylase in cultured fibroblasts.
abstract: 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.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: S
authors.initials: S
authors.lastname: Murad
authors.forename: M C
authors.initials: MC
authors.lastname: Tennant
authors.forename: S R
authors.initials: SR
authors.lastname: Pinnell
mesh_terms: 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
chemical_list: D000959:Antihypertensive Agents; D010880:Piperidines; D011743:Pyrimidines; D008914:Minoxidil; C032727:piperidine; D011393:Procollagen-Proline Dioxygenase; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; C030986:pyrimidine