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

Steroid 5α-reductase is a system of two isozymes (5αR-1 and 5αR-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 5αR inhibitors is thus of great interest for pharmaceutical treatment of these diseases. The synthesis of a novel class of inhibitors for human 5αR-1 and 5αR-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 5αR-2 and in DU-145 human prostatic adenocarcinoma cells toward 5αR-1, in comparison with finasteride (IC50 = 3 nM for 5αR-2 and ∼ 42 nM for 5αR-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. Δ9(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 5αR-2 (IC50 = 4.6 and 4.4 μM, respectively) but more potent inhibitors of 5αR-1 (IC50 = 263 and 299 nM, respectively), whereas 19-nor-10-aza-5α-androstane-3,17-dione (7) was inactive for both the isoenzymes. The best result was achieved with the 9:1 mixture of Δ9(11)- and Δ8(9)-17β-(N-tert-butylcarbamoyl)-19-nor-10-aza-4-androsten-3-one (10a,b) which was a good inhibitor of 5αR-1 and 5αR-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.