Effect of C-ring modifications in benzo[c]quinolizin-3-ones, new selective inhibitors 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 inhibitors 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, 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 5 alpha R-1 and 5 alpha R-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 5 alpha R-1 (IC(50)=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.
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Dipartimento di Chimica Organica U. Schiff and Centro di Studio sulla Chimica e la Struttura dei Composti Eterociclici e loro Applicazioni, C.N.R., Università di Firenze, Via G. Capponi 9, I-50121 Firenze, Italy. guarna@chimorg.unifi.it
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D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics; D058891:5-alpha Reductase Inhibitors; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D011807:Quinolizines / Q000737:chemistry* / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D013329:Structure-Activity Relationship
D058891:5-alpha Reductase Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011807:Quinolizines; D011994:Recombinant Proteins; C435784:octahydrobenzo(c)quinolizin-3-one; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase