title: New 5alpha-reductase inhibitors: in vitro and in vivo effects.
abstract: The enzyme 5alpha-reductase is responsible for the conversion of testosterone (T) to its more potent androgen dihydrotestosterone (DHT). This steroid had been implicated in androgen-dependent diseases such as: benign prostatic hyperplasia, prostate cancer, acne and androgenic alopecia. The inhibition of 5alpha-reductase enzyme offers a potentially useful treatment for these diseases. In this study, we report the synthesis and pharmacological evaluation of several new 3-substituted pregna-4, 16-diene-6, 20-dione derivatives. These compounds were prepared from the commercially available 16-dehydropregnenolone acetate. The biological activity of the new steroidal derivatives was determined in vivo as well as in vitro experiments. In vivo experiments, the anti-androgenic effect of the steroids was demonstrated by the decrease of the weight of the prostate gland of gonadectomized hamster treated with T plus finasteride or the new steroids. The IC50 value of these steroids was determined by measuring the conversion of radio labeled T to DHT. The results of this study carried out with 5alpha-reductase enzyme from hamster and human prostate showed that four of the six steroidal derivatives (5, 7, 9, 10) exhibited much higher 5alpha-reductase inhibitory activity, as indicated by the IC50 values than the presently used Proscar 3 (finasteride). The comparison of the weight of the hamster's prostate gland indicated that compound 5 had a comparable weight decrease as finasteride. The overall data of this study showed very clearly those compounds 5, 7, 9, 10 are good inhibitors for the 5alpha-reductase enzyme.
authors.affiliation: Department of Pharmacy, Faculty of Chemistry, National University of Mexico City, Mexico D.F., Mexico.
authors.forename: Víctor
authors.initials: V
authors.lastname: Pérez-Ornelas
authors.forename: Marisa
authors.initials: M
authors.lastname: Cabeza
authors.forename: Eugene
authors.initials: E
authors.lastname: Bratoeff
authors.forename: Ivonne
authors.initials: I
authors.lastname: Heuze
authors.forename: Mauricio
authors.initials: M
authors.lastname: Sánchez
authors.forename: Elena
authors.initials: E
authors.lastname: Ramírez
authors.forename: Elia
authors.initials: E
authors.lastname: Naranjo-Rodríguez
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D000818:Animals; D042944:Cholestenone 5 alpha-Reductase / Q000037:antagonists & inhibitors*; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018120:Finasteride / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D008297:Male; D008956:Models, Chemical; D011284:Pregnenolone / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D011467:Prostate / Q000187:drug effects; D012997:Solvents
chemical_list: D000726:Androgen Antagonists; D004791:Enzyme Inhibitors; D012997:Solvents; D018120:Finasteride; D011284:Pregnenolone; C007240:dehydropregnenolone acetate; D042944:Cholestenone 5 alpha-Reductase