Received for publication November 16, 2005.
Revised December 12, 2005.
Accepted for publication December 15, 2005.

In vivo Characterization of the Novel Imidazopyridine BYK191023, a Potent and Highly Selective Inhibitor of Inducible Nitric Oxide Synthase

Abstract

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 nitric oxide 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 (MAP) observed in vehicle treated control animals. The vasopressor effect was specific for endotoxaemic 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.

Key words: Hypotension, LPS, Sepsis, iNOS, inhibitor, nitric oxide

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