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INFLAMMATION AND IMMUNOPHARMACOLOGY

In Vivo Characterization of the Novel Imidazopyridine BYK191023 [2-[2-(4-Methoxy-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine], a Potent and Highly Selective Inhibitor of Inducible Nitric-Oxide Synthase

Departments of Pharmacology (M.D.L., D.M., M.E., F.S., J.B.), Biochemistry (R.B., A.S., C.H.), and Chemistry (W.-R.U.), ALTANA Pharma AG, Konstanz, Germany; and Department of Internal Medicine, Justus-Liebig-University, Giessen, Germany (R.T.S.)

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 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 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.

Address correspondence to: Dr. Martin D. Lehner, ALTANA Pharma AG, Byk-Gulden-Strasse 2, 78467 Konstanz, Germany. E-mail: martin.lehner{at}altanapharma.com.

This article has been cited by other articles:

				M. Tiso, A. Strub, C. Hesslinger, C. T. Kenney, R. Boer, and D. J. Stuehr BYK191023 (2-[2-(4-Methoxy-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine) Is an NADPH- and Time-Dependent Irreversible Inhibitor of Inducible Nitric-Oxide Synthase Mol. Pharmacol., April 1, 2008; 73(4): 1244 - 1253. [Abstract] [Full Text] [PDF]