Biochemical and biological studies with 4-aza-steroidal 5α-reductase inhibitors

Summary A series of 4-aza-3-oxosteroids were found to be good inhibitors of steroid 5α-reductase. Two of these compounds. 17 β-N,N -diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one (4-MA) and 4-methyl-4-aza-5α-pregnan-3-one-20(s)-carboxylate, inhibit 5α-reductase competitively with testosterone (T) with K i values of 5 and 1.7 nM, respectively. These 5α-reductase inhibitors also have an affinity to the androgen receptor which is orders of magnitude lower than that of 5α-dihydrotestosterone (DHT), spironolactone and cyproterone acetate. 4-MA decreases the prostatic concentration of DHT and increases that of T in intact male rats and in castrates given T or its propionate derivative. 4-MA is a better inhibitor of T-induced growth than of DHT-induced growth of the prostate and seminal vesicles in castrated rats. It decreases the weight of the prostate and seminal vesicles in intact rats and that of the prostate in dogs. It has no significant antifertility activity in rats. In pregnant rats, 4-MA reduces the ano-genital distance of male fetuses. 4-MA has no significant androgenic, estrogenic, progestational, antiprogestational or antigonadotrophic activity.