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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.

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 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.
AuthorsMartin D Lehner, Degenhard Marx, Rainer Boer, Andreas Strub, Christian Hesslinger, Manfrid Eltze, Wolf-Rüdiger Ulrich, Frank Schwoebel, Ralph Theo Schermuly, Johannes Barsig
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 317 Issue 1 Pg. 181-7 (Apr 2006) ISSN: 0022-3565 [Print] United States
PMID16368897 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 2-(2-(4-methoxypyridin-2-yl)ethyl)-3H-imidazo(4,5-b)pyridine
  • Enzyme Inhibitors
  • Imidazoles
  • Lipopolysaccharides
  • Nitrogen Oxides
  • Pyridines
  • Nitric Oxide Synthase Type II
Topics
  • Animals
  • Blood Pressure (drug effects)
  • Enzyme Inhibitors (pharmacology, therapeutic use)
  • Hemodynamics (drug effects)
  • Hypotension (blood, etiology, physiopathology, prevention & control)
  • Imidazoles (pharmacology, therapeutic use)
  • Lipopolysaccharides
  • Male
  • Nitric Oxide Synthase Type II (antagonists & inhibitors)
  • Nitrogen Oxides (blood)
  • Pyridines (pharmacology, therapeutic use)
  • Rats
  • Rats, Sprague-Dawley
  • Shock, Septic (blood, complications, physiopathology)

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