Pharmacological Characterization of 3-[3-tert-Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic Acid (AM103), a Novel Selective 5-Lipoxygenase-Activating Protein Inhibitor That Reduces Acute and Chronic Inflammation
Leukotrienes (LTs) are proinflammatory lipid mediators synthesized by the conversion of arachidonic acid (AA) to LTA 4 by the enzyme 5-lipoxygenase (5-LO) in the presence of 5-LO-activating protein (FLAP). 3-[3- tert -Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1 H -i...
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| creator | Lorrain, Daniel S Bain, Gretchen Correa, Lucia D Chapman, Charles Broadhead, Alex R Santini, Angelina M Prodanovich, Pat Darlington, Janice V Hutchinson, John H King, Christopher Lee, Catherine Baccei, Christopher Li, Yiwei Arruda, Jeannie M Evans, Jilly F |
| description | Leukotrienes (LTs) are proinflammatory lipid mediators synthesized by the conversion of arachidonic acid (AA) to LTA 4 by the enzyme 5-lipoxygenase (5-LO) in the presence of 5-LO-activating protein (FLAP). 3-[3- tert -Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1 H -indol-2-yl]-2,2-dimethyl-propionic acid (AM103) is a novel selective FLAP inhibitor in development for the treatment of respiratory
conditions such as asthma. In a rat ex vivo whole-blood calcium ionophore-induced LTB 4 assay, AM103 (administered orally at 1 mg/kg) displayed >50% inhibition for up to 6 h with a calculated EC 50 of â¼60 nM. When rat lung was challenged in vivo with calcium ionophore, AM103 inhibited LTB 4 and cysteinyl leukotriene (CysLT) production with ED 50 values of 0.8 and 1 mg/kg, respectively. In this model, the EC 50 derived from plasma AM103 was â¼330 nM for inhibition of both LTB 4 and CysLT. In an acute inflammation setting, AM103 displayed dose-dependent inhibition of LTB 4 , CysLT, and plasma protein extravasation induced by peritoneal zymosan injection. In a model of chronic lung inflammation
using ovalbumin-primed and challenged BALB/c mice, AM103 reduced the concentrations of eosinophil peroxidase, CysLTs, and
interleukin-5 in the bronchoalveolar lavage fluid. Finally, AM103 increased survival time in mice exposed to a lethal intravenous
injection of platelet-activating factor. In summary, AM103 is a novel, potent and selective FLAP inhibitor that has excellent
pharmacodynamic properties in vivo and is effective in animal models of acute and chronic inflammation and in a model of lethal
shock. |
| doi_str_mv | 10.1124/jpet.109.158089 |
| format | Article |
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conditions such as asthma. In a rat ex vivo whole-blood calcium ionophore-induced LTB 4 assay, AM103 (administered orally at 1 mg/kg) displayed >50% inhibition for up to 6 h with a calculated EC 50 of â¼60 nM. When rat lung was challenged in vivo with calcium ionophore, AM103 inhibited LTB 4 and cysteinyl leukotriene (CysLT) production with ED 50 values of 0.8 and 1 mg/kg, respectively. In this model, the EC 50 derived from plasma AM103 was â¼330 nM for inhibition of both LTB 4 and CysLT. In an acute inflammation setting, AM103 displayed dose-dependent inhibition of LTB 4 , CysLT, and plasma protein extravasation induced by peritoneal zymosan injection. In a model of chronic lung inflammation
using ovalbumin-primed and challenged BALB/c mice, AM103 reduced the concentrations of eosinophil peroxidase, CysLTs, and
interleukin-5 in the bronchoalveolar lavage fluid. Finally, AM103 increased survival time in mice exposed to a lethal intravenous
injection of platelet-activating factor. In summary, AM103 is a novel, potent and selective FLAP inhibitor that has excellent
pharmacodynamic properties in vivo and is effective in animal models of acute and chronic inflammation and in a model of lethal
shock.</description><identifier>ISSN: 0022-3565</identifier><identifier>EISSN: 1521-0103</identifier><identifier>DOI: 10.1124/jpet.109.158089</identifier><identifier>PMID: 19749079</identifier><language>eng</language><publisher>United States: American Society for Pharmacology and Experimental Therapeutics</publisher><subject>5-Lipoxygenase-Activating Proteins ; Acute Disease ; Administration, Oral ; Animals ; Anti-Inflammatory Agents, Non-Steroidal - pharmacology ; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use ; Asthma - drug therapy ; Asthma - enzymology ; Asthma - metabolism ; Carrier Proteins - antagonists & inhibitors ; Chronic Disease ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Extravasation of Diagnostic and Therapeutic Materials - drug therapy ; Extravasation of Diagnostic and Therapeutic Materials - enzymology ; Extravasation of Diagnostic and Therapeutic Materials - metabolism ; Female ; Humans ; Indoles - pharmacology ; Indoles - therapeutic use ; Inflammation - drug therapy ; Inflammation - enzymology ; Inflammation - metabolism ; Leukotriene B4 - biosynthesis ; Leukotriene B4 - blood ; Male ; Membrane Proteins - antagonists & inhibitors ; Mice ; Mice, Inbred BALB C ; Pneumonia - drug therapy ; Pneumonia - enzymology ; Pneumonia - metabolism ; Propionates - pharmacology ; Propionates - therapeutic use ; Rats ; Rats, Sprague-Dawley ; Zymosan</subject><ispartof>The Journal of pharmacology and experimental therapeutics, 2009-12, Vol.331 (3), p.1042-1050</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19749079$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lorrain, Daniel S</creatorcontrib><creatorcontrib>Bain, Gretchen</creatorcontrib><creatorcontrib>Correa, Lucia D</creatorcontrib><creatorcontrib>Chapman, Charles</creatorcontrib><creatorcontrib>Broadhead, Alex R</creatorcontrib><creatorcontrib>Santini, Angelina M</creatorcontrib><creatorcontrib>Prodanovich, Pat</creatorcontrib><creatorcontrib>Darlington, Janice V</creatorcontrib><creatorcontrib>Hutchinson, John H</creatorcontrib><creatorcontrib>King, Christopher</creatorcontrib><creatorcontrib>Lee, Catherine</creatorcontrib><creatorcontrib>Baccei, Christopher</creatorcontrib><creatorcontrib>Li, Yiwei</creatorcontrib><creatorcontrib>Arruda, Jeannie M</creatorcontrib><creatorcontrib>Evans, Jilly F</creatorcontrib><title>Pharmacological Characterization of 3-[3-tert-Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic Acid (AM103), a Novel Selective 5-Lipoxygenase-Activating Protein Inhibitor That Reduces Acute and Chronic Inflammation</title><title>The Journal of pharmacology and experimental therapeutics</title><addtitle>J Pharmacol Exp Ther</addtitle><description>Leukotrienes (LTs) are proinflammatory lipid mediators synthesized by the conversion of arachidonic acid (AA) to LTA 4 by the enzyme 5-lipoxygenase (5-LO) in the presence of 5-LO-activating protein (FLAP). 3-[3- tert -Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1 H -indol-2-yl]-2,2-dimethyl-propionic acid (AM103) is a novel selective FLAP inhibitor in development for the treatment of respiratory
conditions such as asthma. In a rat ex vivo whole-blood calcium ionophore-induced LTB 4 assay, AM103 (administered orally at 1 mg/kg) displayed >50% inhibition for up to 6 h with a calculated EC 50 of â¼60 nM. When rat lung was challenged in vivo with calcium ionophore, AM103 inhibited LTB 4 and cysteinyl leukotriene (CysLT) production with ED 50 values of 0.8 and 1 mg/kg, respectively. In this model, the EC 50 derived from plasma AM103 was â¼330 nM for inhibition of both LTB 4 and CysLT. In an acute inflammation setting, AM103 displayed dose-dependent inhibition of LTB 4 , CysLT, and plasma protein extravasation induced by peritoneal zymosan injection. In a model of chronic lung inflammation
using ovalbumin-primed and challenged BALB/c mice, AM103 reduced the concentrations of eosinophil peroxidase, CysLTs, and
interleukin-5 in the bronchoalveolar lavage fluid. Finally, AM103 increased survival time in mice exposed to a lethal intravenous
injection of platelet-activating factor. In summary, AM103 is a novel, potent and selective FLAP inhibitor that has excellent
pharmacodynamic properties in vivo and is effective in animal models of acute and chronic inflammation and in a model of lethal
shock.</description><subject>5-Lipoxygenase-Activating Proteins</subject><subject>Acute Disease</subject><subject>Administration, Oral</subject><subject>Animals</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - therapeutic use</subject><subject>Asthma - drug therapy</subject><subject>Asthma - enzymology</subject><subject>Asthma - metabolism</subject><subject>Carrier Proteins - antagonists & inhibitors</subject><subject>Chronic Disease</subject><subject>Disease Models, Animal</subject><subject>Dose-Response Relationship, Drug</subject><subject>Extravasation of Diagnostic and Therapeutic Materials - drug therapy</subject><subject>Extravasation of Diagnostic and Therapeutic Materials - enzymology</subject><subject>Extravasation of Diagnostic and Therapeutic Materials - metabolism</subject><subject>Female</subject><subject>Humans</subject><subject>Indoles - pharmacology</subject><subject>Indoles - therapeutic use</subject><subject>Inflammation - drug therapy</subject><subject>Inflammation - enzymology</subject><subject>Inflammation - metabolism</subject><subject>Leukotriene B4 - biosynthesis</subject><subject>Leukotriene B4 - blood</subject><subject>Male</subject><subject>Membrane Proteins - antagonists & inhibitors</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Pneumonia - drug therapy</subject><subject>Pneumonia - enzymology</subject><subject>Pneumonia - metabolism</subject><subject>Propionates - pharmacology</subject><subject>Propionates - therapeutic use</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Zymosan</subject><issn>0022-3565</issn><issn>1521-0103</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFUU1v1DAUDAhEl8K5N-Qbu1LfYsf5PG5X_VhpgQrKqaoixx8bV44dEqeQ_nrcZauent7MaOaNXhSdELwkJE6-3HfSLwkulyQtcFG-jmYkjQlggumbaIZxHANNs_Qoej8M9xiTJMnou-iIlHlS4rycvTq5bljfMu6M22nODFqHnXEve_3IvHYWOYUo3FIIkIez0U9mGI1idjJA4DaBeQat9I37O0E39VpoCxQms4Ba2sfJ3EEK82ciDsRBvAByBdoKZ_boHcSnMQj9xAbnrnddCNccrbgWaL76GhotThFD39yDNOinNJJ7_SBRClvdBb-dtGyQsHpCw-F2h65756W2aGMbXWvvenTTMI9-SDFyOQTj0UvErAiV-33UxirD2nZf-0P0VjEzyI-HeRz9uji_WV_B9vvlZr3aQkPS3ENZi5zXOEuUqGlelrTIseKCJ0JkcaIUKTMuMpZSqVSGizwlJCN1plJFCioopsfR5_--ofHvUQ6-avXApTHMSjcOVU6TEBQXeVB-OijHupWi6nrdsn6qnn_5YtXoXfNH97LqXn47VZSSilYEJzH9B9jBsRM</recordid><startdate>20091201</startdate><enddate>20091201</enddate><creator>Lorrain, Daniel S</creator><creator>Bain, Gretchen</creator><creator>Correa, Lucia D</creator><creator>Chapman, Charles</creator><creator>Broadhead, Alex R</creator><creator>Santini, Angelina M</creator><creator>Prodanovich, Pat</creator><creator>Darlington, Janice V</creator><creator>Hutchinson, John H</creator><creator>King, Christopher</creator><creator>Lee, Catherine</creator><creator>Baccei, Christopher</creator><creator>Li, Yiwei</creator><creator>Arruda, Jeannie M</creator><creator>Evans, Jilly F</creator><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>7X8</scope></search><sort><creationdate>20091201</creationdate><title>Pharmacological Characterization of 3-[3-tert-Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic Acid (AM103), a Novel Selective 5-Lipoxygenase-Activating Protein Inhibitor That Reduces Acute and Chronic Inflammation</title><author>Lorrain, Daniel S ; Bain, Gretchen ; Correa, Lucia D ; Chapman, Charles ; Broadhead, Alex R ; Santini, Angelina M ; Prodanovich, Pat ; Darlington, Janice V ; Hutchinson, John H ; King, Christopher ; Lee, Catherine ; Baccei, Christopher ; Li, Yiwei ; Arruda, Jeannie M ; Evans, Jilly F</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h157t-9bd7cb064fdb37993870fcdc4dd624ff196cd6a53eff608751161b6f5f183d303</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>5-Lipoxygenase-Activating Proteins</topic><topic>Acute Disease</topic><topic>Administration, Oral</topic><topic>Animals</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - therapeutic use</topic><topic>Asthma - drug therapy</topic><topic>Asthma - enzymology</topic><topic>Asthma - metabolism</topic><topic>Carrier Proteins - antagonists & inhibitors</topic><topic>Chronic Disease</topic><topic>Disease Models, Animal</topic><topic>Dose-Response Relationship, Drug</topic><topic>Extravasation of Diagnostic and Therapeutic Materials - drug therapy</topic><topic>Extravasation of Diagnostic and Therapeutic Materials - enzymology</topic><topic>Extravasation of Diagnostic and Therapeutic Materials - metabolism</topic><topic>Female</topic><topic>Humans</topic><topic>Indoles - pharmacology</topic><topic>Indoles - therapeutic use</topic><topic>Inflammation - drug therapy</topic><topic>Inflammation - enzymology</topic><topic>Inflammation - metabolism</topic><topic>Leukotriene B4 - biosynthesis</topic><topic>Leukotriene B4 - blood</topic><topic>Male</topic><topic>Membrane Proteins - antagonists & inhibitors</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Pneumonia - drug therapy</topic><topic>Pneumonia - enzymology</topic><topic>Pneumonia - metabolism</topic><topic>Propionates - pharmacology</topic><topic>Propionates - therapeutic use</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Zymosan</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lorrain, Daniel S</creatorcontrib><creatorcontrib>Bain, Gretchen</creatorcontrib><creatorcontrib>Correa, Lucia D</creatorcontrib><creatorcontrib>Chapman, Charles</creatorcontrib><creatorcontrib>Broadhead, Alex R</creatorcontrib><creatorcontrib>Santini, Angelina M</creatorcontrib><creatorcontrib>Prodanovich, Pat</creatorcontrib><creatorcontrib>Darlington, Janice V</creatorcontrib><creatorcontrib>Hutchinson, John H</creatorcontrib><creatorcontrib>King, Christopher</creatorcontrib><creatorcontrib>Lee, Catherine</creatorcontrib><creatorcontrib>Baccei, Christopher</creatorcontrib><creatorcontrib>Li, Yiwei</creatorcontrib><creatorcontrib>Arruda, Jeannie M</creatorcontrib><creatorcontrib>Evans, Jilly F</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of pharmacology and experimental therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lorrain, Daniel S</au><au>Bain, Gretchen</au><au>Correa, Lucia D</au><au>Chapman, Charles</au><au>Broadhead, Alex R</au><au>Santini, Angelina M</au><au>Prodanovich, Pat</au><au>Darlington, Janice V</au><au>Hutchinson, John H</au><au>King, Christopher</au><au>Lee, Catherine</au><au>Baccei, Christopher</au><au>Li, Yiwei</au><au>Arruda, Jeannie M</au><au>Evans, Jilly F</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pharmacological Characterization of 3-[3-tert-Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic Acid (AM103), a Novel Selective 5-Lipoxygenase-Activating Protein Inhibitor That Reduces Acute and Chronic Inflammation</atitle><jtitle>The Journal of pharmacology and experimental therapeutics</jtitle><addtitle>J Pharmacol Exp Ther</addtitle><date>2009-12-01</date><risdate>2009</risdate><volume>331</volume><issue>3</issue><spage>1042</spage><epage>1050</epage><pages>1042-1050</pages><issn>0022-3565</issn><eissn>1521-0103</eissn><abstract>Leukotrienes (LTs) are proinflammatory lipid mediators synthesized by the conversion of arachidonic acid (AA) to LTA 4 by the enzyme 5-lipoxygenase (5-LO) in the presence of 5-LO-activating protein (FLAP). 3-[3- tert -Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1 H -indol-2-yl]-2,2-dimethyl-propionic acid (AM103) is a novel selective FLAP inhibitor in development for the treatment of respiratory
conditions such as asthma. In a rat ex vivo whole-blood calcium ionophore-induced LTB 4 assay, AM103 (administered orally at 1 mg/kg) displayed >50% inhibition for up to 6 h with a calculated EC 50 of â¼60 nM. When rat lung was challenged in vivo with calcium ionophore, AM103 inhibited LTB 4 and cysteinyl leukotriene (CysLT) production with ED 50 values of 0.8 and 1 mg/kg, respectively. In this model, the EC 50 derived from plasma AM103 was â¼330 nM for inhibition of both LTB 4 and CysLT. In an acute inflammation setting, AM103 displayed dose-dependent inhibition of LTB 4 , CysLT, and plasma protein extravasation induced by peritoneal zymosan injection. In a model of chronic lung inflammation
using ovalbumin-primed and challenged BALB/c mice, AM103 reduced the concentrations of eosinophil peroxidase, CysLTs, and
interleukin-5 in the bronchoalveolar lavage fluid. Finally, AM103 increased survival time in mice exposed to a lethal intravenous
injection of platelet-activating factor. In summary, AM103 is a novel, potent and selective FLAP inhibitor that has excellent
pharmacodynamic properties in vivo and is effective in animal models of acute and chronic inflammation and in a model of lethal
shock.</abstract><cop>United States</cop><pub>American Society for Pharmacology and Experimental Therapeutics</pub><pmid>19749079</pmid><doi>10.1124/jpet.109.158089</doi><tpages>9</tpages></addata></record> |
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| ispartof | The Journal of pharmacology and experimental therapeutics, 2009-12, Vol.331 (3), p.1042-1050 |
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| subjects | 5-Lipoxygenase-Activating Proteins Acute Disease Administration, Oral Animals Anti-Inflammatory Agents, Non-Steroidal - pharmacology Anti-Inflammatory Agents, Non-Steroidal - therapeutic use Asthma - drug therapy Asthma - enzymology Asthma - metabolism Carrier Proteins - antagonists & inhibitors Chronic Disease Disease Models, Animal Dose-Response Relationship, Drug Extravasation of Diagnostic and Therapeutic Materials - drug therapy Extravasation of Diagnostic and Therapeutic Materials - enzymology Extravasation of Diagnostic and Therapeutic Materials - metabolism Female Humans Indoles - pharmacology Indoles - therapeutic use Inflammation - drug therapy Inflammation - enzymology Inflammation - metabolism Leukotriene B4 - biosynthesis Leukotriene B4 - blood Male Membrane Proteins - antagonists & inhibitors Mice Mice, Inbred BALB C Pneumonia - drug therapy Pneumonia - enzymology Pneumonia - metabolism Propionates - pharmacology Propionates - therapeutic use Rats Rats, Sprague-Dawley Zymosan |
| title | Pharmacological Characterization of 3-[3-tert-Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic Acid (AM103), a Novel Selective 5-Lipoxygenase-Activating Protein Inhibitor That Reduces Acute and Chronic Inflammation |
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