Evaluation of new pregnane derivatives as 5alpha-reductase inhibitor.
The objective of this study was to synthesize several new pregnane derivatives and evaluate them as antiandrogens. From the commercially available 16-dehydropregnenolone acetate (7), two new steroidal compounds were synthesized: 17alpha-hydroxy-17beta-methyl-16beta-phenyl-D-homoandrosta-1,4,6-triene-3,20-dione (18) and 17alpha-acetoxy-17beta-methyl-16beta-phenyl-D-homoandrosta-1,4,6-triene-3,20-dione (19). The 5alpha-reductase inhibitory effect of the new compounds 18 and 19 together with the previously synthesized intermediates 7, 8, 13, 16, and 17 was determined in three different models: gonadectomized hamster flank organs diameter size, incorporation of [1,2-(14)C]sodium acetate into lipids in flank organs and conversion of [3H]testosterone (T) to [3H]dihydrotestosterone (DHT) by Penicillium crustosum. The evaluation of these steroids was carried out with three different controls: one group was treated with vehicle, the second with T and the third group with T plus finasteride. The pharmacological results from this work demonstrated that T significantly increases the diameter of the pigmented spot on the flank organs (p<0.05) as well as the incorporation of labeled sodium acetate into lipids in gonadectomized hamster flank organs (from 0.125 to 0.255 nmol per gland). In this study we also observed that broth of Penicillium crustosum converted [3H]T to [3H]DHT in a manner comparable to that of the flank organs. All experiments indicated that finasteride as well as steroids 7, 8, 13, 16-19 reduced significantly the conversion of T to DHT in P. crustosum. These compounds also decrease the size of the pigmented spot in the flank organs as well as reducing the incorporation of radiolabeled sodium acetate into lipids; T and the control sample (treated with vehicle only) were used for comparison. Apparently the presence of the 4,6-diene-3,20-dione moiety and also the C-17 ester group produce a higher inhibitory effect on the parameters used. PPThe data from this study indicated also that the three models used for the pharmacological evaluation exhibited comparable results.
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Department of Biological Systems, Agricultural and Animal Production of the Metropolitan University of Mexico, Mexico DF. marisa@cueyatl.uam.mx
Heuze
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Bratoeff
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Ramírez
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Martínez
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R
D058891:5-alpha Reductase Inhibitors; D000818:Animals; D006224:Cricetinae; D013196:Dihydrotestosterone / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008055:Lipids / Q000737:chemistry; D008297:Male; D008647:Mesocricetus; D010407:Penicillium / Q000187:drug effects / Q000201:enzymology; D011278:Pregnanes / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000378:metabolism
D058891:5-alpha Reductase Inhibitors; D004791:Enzyme Inhibitors; D008055:Lipids; D011278:Pregnanes; D013196:Dihydrotestosterone; D013739:Testosterone