PNU 157706, a novel dual type I and II 5alpha-reductase inhibitor.
PNU 157706 is a novel dual inhibitor of 5alpha-reductase (5alpha-R), the enzyme responsible for the conversion of testosterone (T) to 5alpha-dihydrotestosterone (DHT). Tested on a crude preparation of human or rat prostatic 5alpha-R, PNU 157706 caused enzyme inhibition with IC50 values of 20 and 34 nM, respectively, compared to the values of 32 and 58 nM shown by finasteride. Furthermore, PNU 157706 was highly potent in inhibiting human recombinant 5alpha-R type I and II isozymes, showing IC50 values of 3.9 and 1.8 nM and, therefore, it was several folds more potent than finasteride (IC50 values of 313 and 11.3 nM), particularly on the type I isozyme. PNU 157706 was shown to have no binding affinity for the rat prostate androgen receptor (RBA 0.009% that of DHT). In adult male rats, a single oral dose of 10 mg/kg of PNU 157706 caused a marked and longer lasting reduction of prostatic DHT than did finasteride (at 24 h inhibition by 89 and 47%, respectively). In prepubertal, T- or DHT-implanted castrated rats, PNU 157706, given orally for 7 days at the dose of 10 mg/kg/day, markedly reduced ventral prostate weight in T- but not in DHT-implanted animals, thus showing to be devoid of any anti-androgen activity. In adult rats treated orally for 28 days, PNU 157706 resulted markedly more potent (16-fold) than finasteride in reducing prostate weight, the ED50 values being 0.12 and 1.9 mg/kg/day, respectively. These results indicate that PNU 157706 is a promising, potent inhibitor of both type II and I human 5alpha-R with a very marked antiprostatic effect in the rat.
di Salle
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Experimental Endocrinology, Research/Oncology, Pharmacia and Upjohn, Nerviano (MI), Italy. enrico.disalle@eu.pnu.com
Giudici
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D
Radice
A
A
Zaccheo
T
T
Ornati
G
G
Nesi
M
M
Panzeri
A
A
Délos
S
S
Martin
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PM
D058891:5-alpha Reductase Inhibitors; D000284:Administration, Oral; D000736:Androstenes / Q000494:pharmacology*; D000818:Animals; D013196:Dihydrotestosterone / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018120:Finasteride / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D015394:Molecular Structure; D009929:Organ Size / Q000187:drug effects; D011467:Prostate / Q000187:drug effects / Q000201:enzymology*; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D011944:Receptors, Androgen / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism
D058891:5-alpha Reductase Inhibitors; D000736:Androstenes; D004791:Enzyme Inhibitors; D007527:Isoenzymes; C112526:PNU 157706; D011944:Receptors, Androgen; D011994:Recombinant Proteins; D013196:Dihydrotestosterone; D013739:Testosterone; D018120:Finasteride