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

The synthesis and the inhibition potency of octahydro- and decahydrobenzo[c ]quinolizin-3-one derivatives 3-7, as new non-steroidal selective inhibitor s of human enzyme 5 alpha -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, w ith 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 p repared by the Lewis acid-promoted Mannich-Michael tandem reaction of Danis hefsky diene with the appropriate N-t-Boc iminium ion. Inhibition experimen ts were carried out on 5 alphaR-1 and 5 alphaR-2 expressed by CHO cells. Am ong the prepared compounds, octahydrobenzo[c]quinolizin-3-one 3, with a dou ble bond at the position 6a-10a, was a potent and selective inhibitor of hu man 5 alphaR-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 unsatu ration with the enzyme active site could account for the inhibition activit y of these compounds. (C) 2001 Elsevier Science Ltd. All rights reserved.