RT Journal Article
SR Electronic
T1 In Vivo Characterization of the Novel Imidazopyridine BYK191023 [2-[2-(4-Methoxy-pyridin-2-yl)-ethyl]-3<em>H</em>-imidazo[4,5-<em>b</em>]pyridine], a Potent and Highly Selective Inhibitor of Inducible Nitric-Oxide Synthase
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 181
OP 187
DO 10.1124/jpet.105.098673
VO 317
IS 1
A1 Martin D. Lehner
A1 Degenhard Marx
A1 Rainer Boer
A1 Andreas Strub
A1 Christian Hesslinger
A1 Manfrid Eltze
A1 Wolf-Rüdiger Ulrich
A1 Frank Schwoebel
A1 Ralph Theo Schermuly
A1 Johannes Barsig
YR 2006
UL http://jpet.aspetjournals.org/content/317/1/181.abstract
AB 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 (NOx) levels with an ED50 of 14.9 μmol/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 NOx 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. The American Society for Pharmacology and Experimental Therapeutics