title: Azasteroids as inhibitors of testosterone 5 alpha-reductase in mammalian skin.
abstract: Elevated levels of testosterone 5 alpha-reductase (5 alpha-R) and its product, dihydrotestosterone are associated with a number of androgen-dependent skin conditions. A series of 4-azasteroids were tested in vitro as inhibitors of 5 alpha-R in the isolated anagen human hair follicle. Major structural requirements for maximal 5 alpha-R inhibitory activity include a 4-methyl-4-aza moiety and a bulky, lipophilic side chain at C-17. Only one compound, 17 beta-N,N-diethylcarbamyl-4-methyl-4-aza-5 alpha-androstan-3-one (4-MA), was found to be a potent 5 alpha-R inhibitor in all tissues studied: human hair follicles, foreskin (Ki = 3 nM), genital fibroblasts (Ki = 12 nM), and prostate. 17 beta-Hydroxysteroid dehydrogenase activity was not inhibited by 4-MA. With the exception of 4-MA, azasteroid IC50s varied widely in human prostate vs skin, suggesting the possible existence in man of at least two 5 alpha-R isozymes. Finasteride [N(1,1-dimethylethyl)-3-oxo-4-aza-5 alpha-androst-1-ene-17 beta-carboxamide], a delta 1 orally active, specific 5 alpha-R inhibitor exhibiting no affinity for the androgen receptor, was only modestly active in the hair follicle microassay (IC50 = 200 nM). However, it was a potent in vitro inhibitor of human foreskin and prostate 5 alpha-R. Orally administered to rats finasteride inhibited 5 alpha-R in skin. A vasodilator used to treat male pattern baldness (MPB), minoxidil, was found to be a weak inhibitor of human hair follicle 5 alpha-R (IC50 = 1000 nM). 5 alpha-R activity in frontal scalp hair follicles from a MPB subject was four times higher than in occipital follicles. 4-Azasteroids are efficient inhibitors of human skin 5 alpha-R and offer promise for the treatment of acne, hirsutism and MPB.
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065.
authors.forename: T N
authors.initials: TN
authors.lastname: Mellin
authors.forename: R D
authors.initials: RD
authors.lastname: Busch
authors.forename: G H
authors.initials: GH
authors.lastname: Rasmusson
mesh_terms: D058891:5-alpha Reductase Inhibitors; D000818:Animals; D001378:Azasteroids / Q000737:chemistry / Q000494:pharmacology*; D006197:Hair / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D012867:Skin / Q000187:drug effects / Q000201:enzymology*; D013739:Testosterone / Q000378:metabolism
chemical_list: D058891:5-alpha Reductase Inhibitors; D001378:Azasteroids; D013739:Testosterone