DESIGN OF ISOFORM-SELECTIVE INHIBITORS OF NITRIC-OXIDE SYNTHASE

Nitric oxide synthase, the mammalian enzyme catalyzing the oxidation o f L-arginine to L-citrulline and nitric oxide, is present in three iso forms that have distinct physiological roles. Overstimulation or overe xpression of individual nitric oxide synthase isoforms plays a role in a wide range of disorders including septic shock, arthritis, diabetes , ischemia-reperfusion injury, pain and various neurodegenerative dise ases. Animal studies and early clinical trials suggest that nitric oxi de synthase inhibitors could be therapeutic in many of these disorders , but preservation of physiologically important nitric oxide synthase functions might require use of isoform-selective inhibitors. Within th e past few years both amino acid and nonamino acid nitric oxide syntha se inhibitors with pharmacologically useful isoform selectivity have b een reported. Selectivity has been achieved on the basis of initial bi nding affinity and, for mechanism-based inactivators, on the basis of isoform-dependent catalytic activation; particularly interesting are N -5-(1-imino-3-butenyl)-L-ornithine, ARL 17477 1400W and S-(2-aminoethy l)isothiourea.