Benzo[c]quinolizin-3-ones: A Novel Class of Potent and Selective Nonsteroidal Inhibitors of Human Steroid 5α-Reductase 1

The synthesis and biological evaluation of a series of novel, selective inhibitors of isoenzyme 1 of human 5α-reductase (5αR) (EC 1.3.99.5) are reported. The inhibitors are 4aH- (19−29) or 1H-tetrahydrobenzo[c]quinolizin-3-ones (35−47) bearing at positions 1, 4, 5, and 6 a methyl group and at position 8 a hydrogen, methyl group, or chlorine atom. All these compounds were tested toward 5αR-1 and 5αR-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 1H-series having the double bond at position 4,4a on the A ring. The presence of a methyl group at position 4 (as in compounds 39−40 and 45−47), associated with a substituent at position 8, determined the highest inhibition potency (IC50 from 7.6 to 20 nM). Compounds 39 and 40, having Ki values of 5.8 ± 1.8 and 2.7 ± 0.6 nM, respectively, toward 5αR-1 expressed in CHO cells, were also tested toward native 5αR-1 in human scalp and 5αR-2 in human prostate homogenates, in comparison with finasteride and the known 5αR-1-selective inhibitor LY191704, and their mechanism of inhibition was determined. They both inhibited the enzyme through a reversible competitive mechanism and again were selective inhibitors of 5αR-1 with IC50 values of 41 nM. These specific features make these inhibitors suitable candidates for further development as drugs in the treatment of DHT-dependent disorders such as acne and androgenic alopecia in men and hirsutism in women.