12. Androgens: Pharmacodynamics and antagonists. Biochemical and biological studies with 4-aza-steroidal 5 alpha-reductase inhibitors.

A series of 4-aza-3-oxosteroids were found to be good inhibitors of steroid 5 alpha-reductase. Two of these compounds. 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one (4-MA) and 4-methyl-4-aza-5 alpha-pregnan-3-one-20(s)-carboxylate, inhibit 5 alpha-reductase competitively with testosterone (T) with Ki values of 5 and 1.7 nM, respectively. These 5 alpha-reductase inhibitors also have an affinity to the androgen receptor which is orders of magnitude lower than that of 5 alpha-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.