2-IMINOPYRROLIDINES AS POTENT AND SELECTIVE INHIBITORS OF HUMAN INDUCIBLE NITRIC-OXIDE SYNTHASE

A series of substituted 2-iminopyrrolidines has been prepared and show n to be potent and selective inhibitors of the human inducible nitric oxide synthase (hiNOS) isoform versus the human endothelial nitric oxi de synthase (heNOS) and the human neuronal nitric oxide synthase (hnNO S). Simple substitutions at the 3-, 4-, or 5-position afforded more po tent analogues than the parent 2-iminopyrrolidine 1. The effect of rin g substitutions on both potency and selectivity for the different NOS isoforms is described. Substitution at the 4- and 5-positions of the 2 -iminopyrrolidine yielded both potent and selective inhibitors of hiNO S. In particular, (+)-cis-4-methyl-5-pentylpyrrolidin-2-imine, monohyd rochloride (20), displayed potent inhibition of hiNOS (IC50 = 0.25 mu M) and selectivities of 897 (heNOS IC50/hiNOS IC50) and 13 (hnNOS IC50 /hiNOS IC50) Example 20 was shown to be an efficacious inhibitor of NO production in the mouse endotoxin assay. Furthermore, 20 displayed in vivo selectivity, versus heNOS isoform, by not elevating blood pressu re at multiples of the effective dose in the mouse.