Synthesis and pharmacological evaluation of new 16-methyl pregnane derivatives.
The pharmacological activity of several new pregnane derivatives 15-19 were determined on gonadectomized male hamster flank organs, seminal vesicles and in vitro conversion of testosterone (T) to dihydrotestosterone (DHT) as 5alpha-reductase inhibitors. Steroids 15-19 decreased the diameter of the pigmented spot in the flank organs as compared to the T treated animals; in this model, steroids 16 and 19 showed a higher activity than the commercially available finasteride 3. Injection of T increased the weight of the seminal vesicles. Compounds 15-19 when injected together with T decreased the weight of the seminal vesicles thus showing an antiandrogenic effect. The trienone 19 exhibited a considerably higher activity than finasteride. Steroids 15-19 inhibited the in vitro metabolism of [3H]T to [3H]DHT in seminal vesicles homogenates of gonadectomized male hamsters. Compounds 18 and 19 showed a much higher antiandrogenic effect than finasteride. This enhancement of the biological activity could probably be attributed to the coplanarity of the steroidal skeleton as previously observed by our group. The high antiandrogenic activity of the epoxy compound 16 is probably the result of the ring opening of the oxiran ring with the nucleophilic part of the enzyme 5alpha-reductase thus leading to a stable adduct with concomitant deactivation of this enzyme.
Ramirez
Elena
E
Department of Pharmacy, Faculty of Chemistry, UNAM Ciudad Universitaria, Mexico DF, Mexico.
Cabeza
Marisa
M
Heuze
Ivonne
I
Gutiérrez
Edgar
E
Bratoeff
Eugene
E
Membrillo
Marisol
M
Lira
Alfonso
A
D058891:5-alpha Reductase Inhibitors; D000726:Androgen Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D011278:Pregnanes / Q000138:chemical synthesis* / Q000494:pharmacology; D012669:Seminal Vesicles / Q000187:drug effects / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism
D058891:5-alpha Reductase Inhibitors; D000726:Androgen Antagonists; D004791:Enzyme Inhibitors; D011278:Pregnanes; D013739:Testosterone