di Salle E, Giudici D, Radice A, Zaccheo T, Ornati G, Nesi M, Panzeri A, Délos S, Martin P M
Experimental Endocrinology, Research/Oncology, Pharmacia and Upjohn, Nerviano (MI), Italy.
J Steroid Biochem Mol Biol. 1998 Feb;64(3-4):179-86. doi: 10.1016/s0960-0760(97)00158-1.
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.
PNU 157706是一种新型的5α-还原酶（5α-R）双重抑制剂，该酶负责将睾酮（T）转化为5α-二氢睾酮（DHT）。在人或大鼠前列腺5α-R的粗制品上进行测试时，PNU 157706引起酶抑制，IC50值分别为20和34 nM，而非那雄胺显示的值为32和58 nM。此外，PNU 157706在抑制人重组5α-R I型和II型同工酶方面具有高效力，IC50值分别为3.9和1.8 nM，因此，它比非那雄胺（IC50值为313和11.3 nM）效力高几倍，特别是对I型同工酶。PNU 157706对大鼠前列腺雄激素受体没有结合亲和力（相对DHT的RBA为0.009%）。在成年雄性大鼠中，单次口服10 mg/kg的PNU 157706比非那雄胺引起的前列腺DHT降低更显著且持续时间更长（在24小时时分别抑制89%和47%）。在青春期前、植入T或DHT的去势大鼠中，以10 mg/kg/天的剂量口服PNU 157706 7天，在植入T的动物中显著降低了腹侧前列腺重量，但在植入DHT的动物中未降低，因此显示没有任何抗雄激素活性。在成年大鼠中口服治疗长达28天，PNU 157706在减轻前列腺重量方面比非那雄胺显著更有效（16倍），ED50值分别为0.12和1.9 mg/kg/天。这些结果表明，PNU 157706是一种有前景的、高效的人II型和I型5α-R抑制剂，在大鼠中具有非常显著的抗前列腺作用。
