Synthesis and in vitro evaluation of 4-substituted N-(1,1-dimethylethyl)-3-oxo-4-androstene-17 beta-carboxamides as 5 alpha-reductase inhibitors and antiandrogens.
4-Substituted N-(1,1-dimethylethyl)-3-oxo-4-androstene-17 beta-carboxamides with the hydroxy (OH) 3d, mercapto (SH) 3e, chloro (Cl) 3f, and bromo (Br) 3g substituents at the 4-position were prepared in a two-step sequence with overall yields of 21%, 27%, 41%, and 37%, respectively. Compounds 3d-g showed weak inhibitory activity on human type I 5 alpha-reductase (IC50 > or = 700 nM) while they had intermediate inhibitory activity on human type II 5 alpha-reductase at IC50S of 172, 437, 192, and 387 nM, respectively. In androgen-sensitive Shionogi cells, the inhibition of dihydrotestosterone (DHT) stimulatory action on the proliferation of the androgen-sensitive cancer cells by all four compounds was high at IC50S of 170-279 nM compared with 117 nM for hydroxyflutamide. The present data show compounds having both moderate inhibition of human type II 5 alpha-reductase activity and relatively potent antiandrogenic action, two beneficial characteristics in the therapy of androgenic-sensitive diseases.
Li
X
X
Medicinal Chemistry Division, CHUL Research Center, Québec, Canada.
Singh
S M
SM
Côté
J
J
Laplante
S
S
Veilleux
R
R
Labrie
F
F
D058891:5-alpha Reductase Inhibitors; D000726:Androgen Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D000736:Androstenes / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D006801:Humans; D051379:Mice; D014407:Tumor Cells, Cultured
D058891:5-alpha Reductase Inhibitors; D000726:Androgen Antagonists; D000736:Androstenes