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.
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.
Lehner
Martin D
MD
Department of Pharmacology, ALTANA Pharma AG, Konstanz, Germany. martin.lehner@altanapharma.com
Marx
Degenhard
D
Boer
Rainer
R
Strub
Andreas
A
Hesslinger
Christian
C
Eltze
Manfrid
M
Ulrich
Wolf-Rüdiger
WR
Schwoebel
Frank
F
Schermuly
Ralph Theo
RT
Barsig
Johannes
J
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006439:Hemodynamics / Q000187:drug effects; D007022:Hypotension / Q000097:blood / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008070:Lipopolysaccharides; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D009589:Nitrogen Oxides / Q000097:blood; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000097:blood / Q000150:complications / Q000503:physiopathology
C507627:2-(2-(4-methoxypyridin-2-yl)ethyl)-3H-imidazo(4,5-b)pyridine; D004791:Enzyme Inhibitors; D007093:Imidazoles; D008070:Lipopolysaccharides; D009589:Nitrogen Oxides; D011725:Pyridines; D052247:Nitric Oxide Synthase Type II