17-n-n-diethylcarbamoyl-4-methyl-4-azaandrostane-3-one and 4-methyl-4-aza-3-oxopregnane-20-carboxylate

In the present study, we have attempted to determine a detailed representation of the 5 alpha-Reductase (5AR) active site involving the elucidation of the transition state for the steroid delta 4 reduction reaction (the 'NADPH-substrate' complex), onto which steroidal and non-steroidal inhibitors were superimposed. We conclude that: (i) there is a requirement for groups to mimic the steroid substrate A-ring; (ii) the area about C(3), C(4), C(5) and C(6) of T appears to be sterically hindered, and; (iii) the area of the active site about the C(17) of the steroid substrate does not possess hydrogen bonding groups and is not restricted.

Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; 5-alpha Reductase Inhibitors; Azasteroids; Binding Sites; Dihydrotestosterone; Enzyme Inhibitors; Finasteride; Models, Chemical; Models, Molecular; NADP; Pregnanes; Structure-Activity Relationship; Testosterone

The effect of 4-methyl-4-aza-steroidal inhibitors of 5 alpha-reductase has been evaluated on tumor growth in the Noble rat model of prostatic adenocarcinoma. The growth characteristics of the tumor line 2Pr-121D(1) were consistent with heterogeneity of cell types, composed of androgen-sensitive and androgen-insensitive malignant cells. Both sodium 4-methyl-3-oxo-4-aza-5 alpha-pregnane-20 (s)-carboxylate and 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5 and 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one significantly retarded tumor progression. Each agent increased tumor volume doubling time by approximately 62%. On the basis of their similarities to female rats and male castrate group, in terms of growth rate, tumor doubling time, and histologic characteristics, the treatments with the 4-methyl-4-aza-steroids appeared to produce effects common to both castration and estrogenization (chronic administration of pharmacologic doses of estrogen). The failure of 5 alpha-reductase inhibitors to be active as antiprostatic agents in vivo has hitherto detracted from their use of therapeutic agents. Present studies demonstrate that the 4-methyl-4-aza-steroidal inhibitors of 5 alpha-reductase may represent an alternative to orchiectomy and chronic estrogen therapy for the management of the hormone-dependent phase of prostate cancer.

Topics: 5-alpha Reductase Inhibitors; Animals; Azasteroids; Castration; Dihydrotestosterone; Male; Organ Size; Oxidoreductases; Pregnanes; Prostate; Prostatic Neoplasms; Rats; Rats, Inbred Strains; Steroids, Heterocyclic

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.

Topics: 5-alpha Reductase Inhibitors; Animals; Azasteroids; Binding, Competitive; Dihydrotestosterone; Kinetics; Male; Oxidoreductases; Pregnanes; Prostate; Rats; Receptors, Androgen; Steroids, Heterocyclic; Structure-Activity Relationship