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]-3H-imidazo[4,5-b]pyridine (BYK191023) showed half-maximal inhibition of crudely purified human inducible (iNOS), neuronal (n...

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Veröffentlicht in:Molecular pharmacology 2006-01, Vol.69 (1), p.328-337
Hauptverfasser: Strub, Andreas, Ulrich, Wolf-Rüdiger, Hesslinger, Christian, Eltze, Manfrid, Fuchß, Thomas, Strassner, Jochen, Strand, Susanne, Lehner, Martin D., Boer, Rainer
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container_issue 1
container_start_page 328
container_title Molecular pharmacology
container_volume 69
creator Strub, Andreas
Ulrich, Wolf-Rüdiger
Hesslinger, Christian
Eltze, Manfrid
Fuchß, Thomas
Strassner, Jochen
Strand, Susanne
Lehner, Martin D.
Boer, Rainer
description 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.
doi_str_mv 10.1124/mol.105.017087
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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 &gt;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 &gt; 100 μM), and nNOS (field-stimulated relaxation of phenylephrine-precontracted rabbit corpus cavernosum; IC50 &gt; 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. 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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 &gt;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 &gt; 100 μM), and nNOS (field-stimulated relaxation of phenylephrine-precontracted rabbit corpus cavernosum; IC50 &gt; 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.</description><subject>Animals</subject><subject>Aorta, Thoracic - drug effects</subject><subject>Aorta, Thoracic - enzymology</subject><subject>Arginine - pharmacology</subject><subject>Cell Line</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Humans</subject><subject>Imidazoles - chemistry</subject><subject>Imidazoles - pharmacology</subject><subject>In Vitro Techniques</subject><subject>Male</subject><subject>Nitric Oxide Synthase Type II - antagonists &amp; inhibitors</subject><subject>Nitric Oxide Synthase Type III - antagonists &amp; inhibitors</subject><subject>Pyridines - chemistry</subject><subject>Pyridines - pharmacology</subject><subject>Rabbits</subject><subject>Radioligand Assay</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Structure-Activity Relationship</subject><issn>0026-895X</issn><issn>1521-0111</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kMFu1DAQhi0EokvhyhH5gtRKePHYceIcS0W7Kwo9tEigqrISe9IYJeuVky4Nr8RL4iorOHHyaOb7rJmfkNfAlwAie9-HbglcLTkUXBdPyAKUAMYB4ClZcC5ypkv17YC8GIYfnEOmNH9ODiAXQpaqWJDf1y3SL2GHHV333lW_wnaK3vkNUsFuBDvK2Gcc2_Awsf2ACTZ1xyw1p-6WyRXzs3eTvVOsvv2rH334_glK4EIe0_VAK7ryd2030Svs0I5-h3S9aX3txxBpaOjYPjbcvfV1lzbyY_SWXT54h_Rq2oxtNeBL8qypugFf7d9D8vXs4_Xpil1cnq9PTy6YlaIYmbBaaZC5tg4KzFypZFGITKEF57QWWZ3noCxvMuE0iFrWtcwdyKZGrLAq5SFZzv_aGIYhYmO20fdVnAxw85i6SamnWpk59SS8mYXtfd2j-4fvY07A2xloUwY_fUSzbavYVzZ04W4yeWnASKETp2cO03k7j9EM1uPGokuOHY0L_n87_AEKKJ0j</recordid><startdate>200601</startdate><enddate>200601</enddate><creator>Strub, Andreas</creator><creator>Ulrich, Wolf-Rüdiger</creator><creator>Hesslinger, Christian</creator><creator>Eltze, Manfrid</creator><creator>Fuchß, Thomas</creator><creator>Strassner, Jochen</creator><creator>Strand, Susanne</creator><creator>Lehner, Martin D.</creator><creator>Boer, Rainer</creator><general>Elsevier Inc</general><general>American Society for Pharmacology and Experimental Therapeutics</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>200601</creationdate><title>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</title><author>Strub, Andreas ; 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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 &gt;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 &gt; 100 μM), and nNOS (field-stimulated relaxation of phenylephrine-precontracted rabbit corpus cavernosum; IC50 &gt; 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.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>16223957</pmid><doi>10.1124/mol.105.017087</doi><tpages>10</tpages></addata></record>
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subjects Animals
Aorta, Thoracic - drug effects
Aorta, Thoracic - enzymology
Arginine - pharmacology
Cell Line
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Humans
Imidazoles - chemistry
Imidazoles - pharmacology
In Vitro Techniques
Male
Nitric Oxide Synthase Type II - antagonists & inhibitors
Nitric Oxide Synthase Type III - antagonists & inhibitors
Pyridines - chemistry
Pyridines - pharmacology
Rabbits
Radioligand Assay
Rats
Rats, Wistar
Structure-Activity Relationship
title 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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