Document Report Card

ID: ALA1131208

Journal: J Med Chem

Title: Substituted 2-iminopiperidines as inhibitors of human nitric oxide synthase isoforms.

Authors: Webber RK, Metz S, Moore WM, Connor JR, Currie MG, Fok KF, Hagen TJ, Hansen DW, Jerome GM, Manning PT, Pitzele BS, Toth MV, Trivedi M, Zupec ME, Tjoeng FS.

Abstract: A series of analogues of 2-iminopiperidine have been prepared and shown to be potent inhibitors of the human nitric oxide synthase (NOS) isoforms. Methyl substitutions on the 4-position (3) or 4- and 6-positions (8) afforded the most potent analogues. These compounds exhibited IC50 values of 0.1 and 0.08 microM, respectively, for hiNOS inhibition. Substitution with cyclohexylmethyl at the 6-position (13) afforded an inhibitor 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 endotoxin assay. This series of 2-iminopiperidines were prepared via the described synthetic methodologies. The effect of ring substitutions on potency and selectivity for this class of cyclic amidines as NOS inhibitors is described.

CiteXplore: 9438025

DOI: 10.1021/jm9705059