Effect of C-ring modifications in benzo[c]quinolizin-3-ones, new selective inhibitors of human 5α-reductase 1

The synthesis and the inhibition potency of octahydro- and decahydrobenzo[c]quinolizin-3-one derivatives 3–7, as new non-steroidal selective inhibitors of human enzyme 5α-reductase type 1, are reported. These compounds differ from the recently reported benzo[c]quinolizin-3-one inhibitors 2 by the presence of a fully or partially saturated C-ring. Compounds 3 and 4, with a double bond in the C-ring, were prepared by sequential rearrangement-annulation of isoxazolines 19 and 20. C-ring saturated compounds 5–7 were prepared by the Lewis acid-promoted Mannich-Michael tandem reaction of Danishefsky diene with the appropriate N-t-Boc iminium ion. Inhibition experiments were carried out on 5αR-1 and 5αR-2 expressed by CHO cells. Among the prepared compounds, octahydrobenzo[c]quinolizin-3-one 3, with a double bond at the position 6a–10a, was a potent and selective inhibitor of human 5αR-1 (IC50=58 nM). The introduction of a tert-butylcarboxyamide at the position 8 (compound 4) was deleterious for the inhibition activity. The lack of the double bond in the C-ring reduced strongly the inhibition activity of compounds 5–7. The extended planarity of the most potent benzo[c]quinolizin-3-ones as well as favorable interactions of the C-ring unsaturation with the enzyme active site could account for the inhibition activity of these compounds.