19-Nor-10-azasteroids: A Novel Class of Inhibitors for Human Steroid 5?-Reductases 1 and 2

Steroid 5 alpha-reductase is a system of two isozymes (5 alpha R-1 and 5 alpha R-2) which catalyzes the NADPH-dependent reduction of testosterone to dihydrotestosterone in many androgen sensitive tissues and which is related to several human endocrine diseases such as benign prostatic hyperplasia (BPH), prostatic cancer, acne, alopecia, pattern baldness in men and hirsutism in women. The discovery of new potent and selective 5 alpha R inhibitors is thus of great interest for pharmaceutical treatment of these diseases. The synthesis of a novel class of inhibitors for human 5 alpha R-1 and 5 alpha R-2, having the 19-nor-10-azasteroid skeleton, is described. The inhibitory potency of the 19-nor-10-azasteroids was determined in homogenates of human hypertrophic prostates toward 5 alpha R-2 and in DU-145 human prostatic adenocarcinoma cells toward 5 alpha R-1, in comparison with finasteride (IC50 = 3 nM for 5 alpha R-2 and similar to 42 nM for 5 alpha R-1), a drug which is currently used for BPH treatment. The inhibition potency was dependent on the type of substituent at position 17 and on the presence and position of the unsaturation in the A and C rings. Delta(9(11))-19-Nor-10-azaandrost-4-ene-3,17-dione (or 10-azaestra-4,9(11)-diene-3,17-dione) (4a) and 19-nor-10-azaandrost-4-ene-3,17-dione (5) were weak inhibitors of 5 alpha R-2 (IC50 = 4.6 and 4.4 mu M, respectively) but more potent inhibitors of 5 alpha R-1 (IC50 = 263 and 299 nM, respectively), whereas 19-nor-10-aza-5 alpha-androstane-3,17-dione (7) was inactive for both the isoenzymes. The best result was achieved with the 9:1 mixture of Delta(9(11))- and Delta(8(9))-17 beta-(N-tertbutylcarbamoyl)-19-nor-10-aza-4-androsten-3-one (10a,b) which was a good inhibitor of 5 alpha R-1 and 5 alpha R-2 (IC50 = 127 and 122 nM, respectively), with a potency very close to that of finasteride. The results of ab initio calculations suggest that the inhibition potency of 19-nor-10-azasteroids could be directly related to the nucleophilicity of the carbonyl group in the 3-position