SUBSTITUTED 2-IMINOPIPERIDINES AS INHIBITORS OF HUMAN NITRIC-OXIDE SYNTHASE ISOFORMS

A series of analogues of 2-iminopiperidine have been prepared and show n to be potent inhibitors of the human nitric oxide synthase (NOS) iso forms. Methyl substitutions on the 4-position (3) or 4- and 6-position s (8) afforded the most potent analogues. These compounds exibited IC5 0 values of 0.1 and 0.08 mu M, respectively, for hiNOS inhibition. Sub stitution with cyclohexylmethyl at the 6-position (13) afforded an inh ibitor that showed the best selectivity for hiNOS versus heNOS (heNOS IC50/hiNOS IC50 = 64). Following oral administration, inhibitors were found to decrease serum nitrite/nitrate levels in an in vivo rat endot oxin assay. This series of 2-iminopiperidines were prepared via the de scribed synthetic methodologies. The effect of ring substitutions on p otency and selectivity for this class of cyclic amidines as NOS inhibi tors is described.