Loading…
The Novel Imidazopyridine 2-[2-(4-Methoxy-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine (BYK191023) Is a Highly Selective Inhibitor of the Inducible Nitric-Oxide Synthase
We have identified imidazopyridine derivatives as a novel class of NO synthase inhibitors with high selectivity for the inducible isoform. 2-[2-(4-Methoxy-pyridin-2-yl)-ethyl]-3 H -imidazo[4,5- b ]pyridine (BYK191023) showed half-maximal inhibition of crudely purified human inducible (iNOS), neurona...
Saved in:
Published in: | Molecular pharmacology 2006-01, Vol.69 (1), p.328 |
---|---|
Main Authors: | , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Online Access: | Get full text |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
Summary: | We have identified imidazopyridine derivatives as a novel class of NO synthase inhibitors with high selectivity for the inducible
isoform. 2-[2-(4-Methoxy-pyridin-2-yl)-ethyl]-3 H -imidazo[4,5- b ]pyridine (BYK191023) showed half-maximal inhibition of crudely purified human inducible (iNOS), neuronal (nNOS), and endothelial
(eNOS) NO synthases at 86 nM, 17 μM, and 162 μM, respectively. Inhibition of inducible NO synthase was competitive with l -arginine, pointing to an interaction of BYK191023 with the catalytic center of the enzyme. In radioligand and surface plasmon
resonance experiments, BYK191023 exhibited an affinity for iNOS, nNOS, and eNOS of 450 nM, 30 μM, and >500 μM, respectively.
Inhibition of cellular nitrate/nitrite synthesis in RAW, rat mesangium, and human embryonic kidney 293 cells after iNOS induction
showed 40- to 100-fold higher IC 50 values than at the isolated enzyme, in agreement with the much higher l -arginine concentrations in cell culture media and inside intact cells. BYK191023 did not show any toxicity in various rodent
and human cell lines up to high micromolar concentrations. The inhibitory potency of BYK191023 was tested in isolated organ
models of iNOS (lipopolysaccharide-treated and phenylephrine-precontracted rat aorta; IC 50 = 7 μM), eNOS (arecaidine propargyl ester-induced relaxation of phenylephrine-precontracted rat aorta; IC 50 > 100 μM), and nNOS (field-stimulated relaxation of phenylephrine-precontracted rabbit corpus cavernosum; IC 50 > 100 μM). These data confirm the high selectivity of BYK191023 for iNOS over eNOS and nNOS found at isolated enzymes. In
summary, we have identified a new highly selective iNOS inhibitor structurally unrelated to known compounds and l -arginine. BYK191023 is a valuable tool for the investigation of iNOS-mediated effects in vitro and in vivo. |
---|---|
ISSN: | 0026-895X 1521-0111 |
DOI: | 10.1124/mol.105.017087 |