NOVEL AROMATASE AND 5-ALPHA-REDUCTASE INHIBITORS

Inhibitors of aromatase and ja-reductase may be Of use for the therapy of postmenopausal breast cancer and benign prostatic hyperplasia, res pectively. FCE 27993 is a novel steroidal irreversible aromatase inhib itor structurally related to exemestane (FCE 24304). The compound was found to be a very potent competitive inhibitor of human placental aro matase, with a K-i of 7.2 nM (4.3 nM for exemestane). In preincubation studies with placental aromatase FCE 27993, like exemestane, was foun d to cause time-dependent inhibition with a higher rate of inactivatio n (t(1/2) 4.5 vs 15.1 min) and a similar K-i(inact) (56 vs 66 nM). The compound was found to have a very low binding affinity to the androge n receptor (RBA 0.09% of dihydrotestosterone) and, in contrast to exem estane, no androgenic activity up to 100 mg/kg/day s.c. in immature ca strated rats. Among a series of novel 4-azasteroids with fluoro-substi tuted-17 beta-amidic side chains, three compounds, namely FCE 28260, F CE 28175 and FCE 27837, were identified as potent in vitro and in vivo inhibitors of prostatic 5a-reductase. Their IC50 values were found to be 16, 38 and 51 nM for the inhibition of the human enzyme, and 15, 2 0 and 60 nM for the inhibition of the rat enzyme, respectively. When g iven orally for 7 days in castrated and testosterone (Silastic implant s) supplemented rats, the new compounds were very effective in reducin g prostate growth. At a dose of 0.3 mg/kg/day inhibitions of 42, 36 an d 41% were caused by FCE 28260, FCE 28175 and FCE 27837, respectively.