Benzo[c]quinolizin-3-ones: A novel class of potent and selective nonsteroidal inhibitors of human steroid 5 alpha-reductase

The synthesis and biological evaluation of a series of novel, selective inh ibitors of isoenzyme 1 of human 5 alpha-reductase (5 alpha R) (EC 1.3.99.5) are reported. The inhibitors are 4aH- (19-29) or 1H-tetrahydrobenzo[c]quin olizin-3-ones (35-47) bearing at positions 1, 4, 5, and 6 a methyl group an d at position 8 a hydrogen, methyl group, or chlorine atom. All these compo unds were tested toward 5 alpha R-1 and 5 alpha R-2 expressed in CHO cells (CHO 1827 and CHO 1829, respectively) resulting in selective inhibitors of the type 1 isoenzyme, with inhibitory potencies (IC50) ranging from 7.6 to 9100 nM. The inhibitors of the 4aH-series, having a double bond at position 1,2, were generally less active than the corresponding inhibitors of the 1 H-series having the double bond at position 4,4a on the A ring. The presenc e of a methyl group at position 4 las in compounds 39-40 and 45-47), associ ated with a substituent at position 8, determined the highest inhibition po tency (IC50 from 7.6 to 20 nM). Compounds 39 and 40, having K-i values of 5 .8 +/- 1.8 and 2.7 +/- 0.6 nM, respectively, toward 5 alpha R-1 expressed i n CHO cells, were also tested toward native 5 alpha R-1 in human scalp and 5 alpha R-2 in human prostate homogenates, in comparison with finasteride a nd the known 5 alpha R-1-selective inhibitor LY191704, and their mechanism of inhibition was determined. They both inhibited the enzyme through a reve rsible competitive mechanism and again were selective inhibitors of 5 alpha R-1 with IC50 values of 41 nM. These specific features make these inhibito rs suitable candidates for further development as drugs in the treatment of DHT-dependent disorders such as acne and androgenic alopecia in men and hi rsutism in women.