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Research ArticleArticle

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

Andreas Strub, Wolf-Rüdiger Ulrich, Christian Hesslinger, Manfrid Eltze, Thomas Fuchß, Jochen Strassner, Susanne Strand, Martin D. Lehner and Rainer Boer
Molecular Pharmacology January 2006, 69 (1) 328-337; DOI: https://doi.org/10.1124/mol.105.017087
Andreas Strub
Departments of Biochemistry, Chemistry and Pharmacology, ALTANA Pharma AG, Konstanz, Germany (A.S., W.-R.U., C.H., M.E., T.F., J.S., M.D.L., R.B.); and Department of Internal Medicine, Johannes Gutenberg University, Mainz, Germany (S.S.)
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Wolf-Rüdiger Ulrich
Departments of Biochemistry, Chemistry and Pharmacology, ALTANA Pharma AG, Konstanz, Germany (A.S., W.-R.U., C.H., M.E., T.F., J.S., M.D.L., R.B.); and Department of Internal Medicine, Johannes Gutenberg University, Mainz, Germany (S.S.)
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Christian Hesslinger
Departments of Biochemistry, Chemistry and Pharmacology, ALTANA Pharma AG, Konstanz, Germany (A.S., W.-R.U., C.H., M.E., T.F., J.S., M.D.L., R.B.); and Department of Internal Medicine, Johannes Gutenberg University, Mainz, Germany (S.S.)
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Manfrid Eltze
Departments of Biochemistry, Chemistry and Pharmacology, ALTANA Pharma AG, Konstanz, Germany (A.S., W.-R.U., C.H., M.E., T.F., J.S., M.D.L., R.B.); and Department of Internal Medicine, Johannes Gutenberg University, Mainz, Germany (S.S.)
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Thomas Fuchß
Departments of Biochemistry, Chemistry and Pharmacology, ALTANA Pharma AG, Konstanz, Germany (A.S., W.-R.U., C.H., M.E., T.F., J.S., M.D.L., R.B.); and Department of Internal Medicine, Johannes Gutenberg University, Mainz, Germany (S.S.)
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Jochen Strassner
Departments of Biochemistry, Chemistry and Pharmacology, ALTANA Pharma AG, Konstanz, Germany (A.S., W.-R.U., C.H., M.E., T.F., J.S., M.D.L., R.B.); and Department of Internal Medicine, Johannes Gutenberg University, Mainz, Germany (S.S.)
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Susanne Strand
Departments of Biochemistry, Chemistry and Pharmacology, ALTANA Pharma AG, Konstanz, Germany (A.S., W.-R.U., C.H., M.E., T.F., J.S., M.D.L., R.B.); and Department of Internal Medicine, Johannes Gutenberg University, Mainz, Germany (S.S.)
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Martin D. Lehner
Departments of Biochemistry, Chemistry and Pharmacology, ALTANA Pharma AG, Konstanz, Germany (A.S., W.-R.U., C.H., M.E., T.F., J.S., M.D.L., R.B.); and Department of Internal Medicine, Johannes Gutenberg University, Mainz, Germany (S.S.)
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Rainer Boer
Departments of Biochemistry, Chemistry and Pharmacology, ALTANA Pharma AG, Konstanz, Germany (A.S., W.-R.U., C.H., M.E., T.F., J.S., M.D.L., R.B.); and Department of Internal Medicine, Johannes Gutenberg University, Mainz, Germany (S.S.)
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Abstract

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]-3H-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 IC50 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; IC50 = 7 μM), eNOS (arecaidine propargyl ester-induced relaxation of phenylephrine-precontracted rat aorta; IC50 > 100 μM), and nNOS (field-stimulated relaxation of phenylephrine-precontracted rabbit corpus cavernosum; IC50 > 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.

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Molecular Pharmacology: 69 (1)
Molecular Pharmacology
Vol. 69, Issue 1
1 Jan 2006
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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
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Research ArticleArticle

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

Andreas Strub, Wolf-Rüdiger Ulrich, Christian Hesslinger, Manfrid Eltze, Thomas Fuchß, Jochen Strassner, Susanne Strand, Martin D. Lehner and Rainer Boer
Molecular Pharmacology January 1, 2006, 69 (1) 328-337; DOI: https://doi.org/10.1124/mol.105.017087

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Research ArticleArticle

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

Andreas Strub, Wolf-Rüdiger Ulrich, Christian Hesslinger, Manfrid Eltze, Thomas Fuchß, Jochen Strassner, Susanne Strand, Martin D. Lehner and Rainer Boer
Molecular Pharmacology January 1, 2006, 69 (1) 328-337; DOI: https://doi.org/10.1124/mol.105.017087
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