Br. Babu et Ow. Griffith, DESIGN OF ISOFORM-SELECTIVE INHIBITORS OF NITRIC-OXIDE SYNTHASE, Current opinion in chemical biology, 2(4), 1998, pp. 491-500
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.