New progesterone esters as 5alpha-reductase inhibitors.
The pharmacological activity of four new progesterone derivatives: 4-bromo-17alpha-(p-fluorobenzoyloxy)-4-pregnene-3,20-dione (7), 4-bromo-17alpha-(p-bromobenzoyloxy)-4-pregnene-3,20-dione (8), 4-bromo-17alpha-(p-chlorobenzoyloxy)-pregnene-3,20-dione (9) and 4-bromo-17alpha-(p-toluoyloxy)-4-pregnene-3,20-dione (10) was determined. These compounds were evaluated as 5alpha-reductase inhibitors on gonadectomized hamster seminal vesicles and flank organs. The pharmacological data of this study indicate that compounds 7 and 9 having at C-17 p-fluorobenzoyloxy and p-chlorobenzoyloxy ester functions respectively showed the highest antiandrogenic effect as measured by the reduction of the weight of the seminal vesicles. In the flank organ model, the same compounds 7 and 9 exhibited a smaller diameter, 1.8 and 1.0 mm, respectively, than the commercially available finasteride 3 (2.3 mm), thus indicating a higher inhibitory effect on 5alpha-reductase enzyme. Steroid 7 showed a higher inhibitory activity on the conversion of T to DHT (Fig. 3) than the presently used finasteride, thus indicating a higher antiandrogenic effect. The nonsubstituted benzoyloxy ester (compound 15) showed a lower antiandrogenic activity as measured in the seminal vesicles model than the p-substituted benzoyloxy compounds.
Cabeza
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Department of Biological Systems, Metropolitan University-Xochimilco, Mexico DF, Mexico. marisa@cueyatl.uam.mx
Heuze
I
I
Bratoeff
E
E
Murillo
E
E
Ramirez
E
E
Lira
A
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; D004952:Esters / Q000138:chemical synthesis / Q000494:pharmacology; D007202:Indicators and Reagents; D008297:Male; D008647:Mesocricetus; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D010858:Pigmentation / Q000187:drug effects; D011374:Progesterone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D012669:Seminal Vesicles / Q000187:drug effects / Q000378:metabolism
D058891:5-alpha Reductase Inhibitors; D000726:Androgen Antagonists; D004791:Enzyme Inhibitors; D004952:Esters; D007202:Indicators and Reagents; D011374:Progesterone