Excessive release of
nitric oxide from
inducible nitric-oxide synthase (iNOS) has been postulated to contribute to pathology in a number of inflammatory diseases. We recently identified
imidazopyridine derivatives as a novel class of potent nitricoxide synthase inhibitors with high selectivity for the inducible
isoform. In the present study, we tested the in vivo potency of
BYK191023 [2-[2-(4-methoxy-pyridin-2-yl)-ethyl]-3H-imidazo-[4,5-
b]pyridine], a selected member of this inhibitor class, in three different rat models of
lipopolysaccharide-induced systemic
inflammation. Delayed administration of
BYK191023 dose-dependently suppressed the
lipopolysaccharide-induced increase in plasma
nitrate/
nitrite (NO(x)) levels with an ED(50) of 14.9 micromol/kg/h. In a model of systemic
hypotension following high-dose
lipopolysaccharide challenge, curative administration of
BYK191023 at a dose that inhibited 83% of the NO(x) increase completely prevented the gradual decrease in mean arterial blood pressure observed in vehicle-treated control animals. The vasopressor effect was specific for endotoxemic animals since
BYK191023 did not affect blood pressure in saline-challenged controls. In addition, in a model of
lipopolysaccharide-induced vascular hyporesponsiveness,
BYK191023 infusion partially restored normal blood pressure responses to
norepinephrine and
sodium nitroprusside via an
l-arginine competitive mechanism. Taken together,
BYK191023 is a member of a novel class of highly
isoform-selective iNOS inhibitors with promising in vivo activity suitable for mechanistic studies on the role of selective iNOS inhibition as well as clinical development.