Optimization of Chromone-2-carboxamide Melanin Concentrating Hormone Receptor 1 Antagonists: Assessment of Potency, Efficacy, and Cardiovascular Safety
Evaluation of multiple structurally distinct series of melanin concentrating hormone receptor 1 antagonists in an anesthetized rat cardiovascualar assay led to the identification of a chromone-2-carboxamide series as having excellent safety against the chosen cardiovascular endpoints at high drug co...
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| Veröffentlicht in: | Journal of medicinal chemistry 2006-11, Vol.49 (22), p.6569-6584 |
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| container_title | Journal of medicinal chemistry |
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| creator | Lynch, John K Freeman, Jennifer C Judd, Andrew S Iyengar, Rajesh Mulhern, Mathew Zhao, Gang Napier, James J Wodka, Dariusz Brodjian, Sevan Dayton, Brian D Falls, Doug Ogiela, Christopher Reilly, Regina M Campbell, Thomas J Polakowski, James S Hernandez, Lisa Marsh, Kennan C Shapiro, Robin Knourek-Segel, Victoria Droz, Brian Bush, Eugene Brune, Michael Preusser, Lee C Fryer, Ryan M Reinhart, Glenn A Houseman, Kathryn Diaz, Gilbert Mikhail, Ann Limberis, James T Sham, Hing L Collins, Christine A Kym, Philip R |
| description | Evaluation of multiple structurally distinct series of melanin concentrating hormone receptor 1 antagonists in an anesthetized rat cardiovascualar assay led to the identification of a chromone-2-carboxamide series as having excellent safety against the chosen cardiovascular endpoints at high drug concentrations in the plasma and brain. Optimization of this series led to considerable improvements in affinity, functional potency, and pharmacokinetic profile. This led to the identification of a 7-fluorochromone-2-carboxamide (22) that was orally efficacious in a diet-induced obese mouse model, retained a favorable cardiovascular profile in rat, and demonstrated dramatic improvement in effects on mean arterial pressure in our dog cardiovascular model compared to other series reported by our group. However, this analogue also led to prolongation of the QT interval in the dog that was linked to affinity for hERG channel and unexpectedly potent functional blockade of this ion channel. |
| doi_str_mv | 10.1021/jm060683e |
| format | Article |
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Optimization of this series led to considerable improvements in affinity, functional potency, and pharmacokinetic profile. This led to the identification of a 7-fluorochromone-2-carboxamide (22) that was orally efficacious in a diet-induced obese mouse model, retained a favorable cardiovascular profile in rat, and demonstrated dramatic improvement in effects on mean arterial pressure in our dog cardiovascular model compared to other series reported by our group. However, this analogue also led to prolongation of the QT interval in the dog that was linked to affinity for hERG channel and unexpectedly potent functional blockade of this ion channel.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm060683e</identifier><identifier>PMID: 17064075</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Acylation ; Animals ; Area Under Curve ; Benzodioxoles - pharmacokinetics ; Benzodioxoles - pharmacology ; Benzodioxoles - toxicity ; Biological and medical sciences ; Blood Pressure - drug effects ; Body Weight - drug effects ; Calcium - metabolism ; Cardiovascular Diseases - chemically induced ; Cell Line ; Chromones - pharmacokinetics ; Chromones - pharmacology ; Chromones - toxicity ; Dogs ; Electrocardiography - drug effects ; Female ; Half-Life ; Heart Rate - drug effects ; Hormones. Endocrine system ; Indicators and Reagents ; Medical sciences ; Mice ; Mice, Inbred C57BL ; Pharmacology. Drug treatments ; Potassium Channels - drug effects ; Potassium Channels - metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, Somatostatin - antagonists & inhibitors ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2006-11, Vol.49 (22), p.6569-6584</ispartof><rights>Copyright © 2006 American Chemical Society</rights><rights>2007 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a381t-9e99114cbc6b1f1694d1b5eb1996a70c736d3b01e905e56d41a1945a63afe013</citedby><cites>FETCH-LOGICAL-a381t-9e99114cbc6b1f1694d1b5eb1996a70c736d3b01e905e56d41a1945a63afe013</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm060683e$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm060683e$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=18237030$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17064075$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lynch, John K</creatorcontrib><creatorcontrib>Freeman, Jennifer C</creatorcontrib><creatorcontrib>Judd, Andrew S</creatorcontrib><creatorcontrib>Iyengar, Rajesh</creatorcontrib><creatorcontrib>Mulhern, Mathew</creatorcontrib><creatorcontrib>Zhao, Gang</creatorcontrib><creatorcontrib>Napier, James J</creatorcontrib><creatorcontrib>Wodka, Dariusz</creatorcontrib><creatorcontrib>Brodjian, Sevan</creatorcontrib><creatorcontrib>Dayton, Brian D</creatorcontrib><creatorcontrib>Falls, Doug</creatorcontrib><creatorcontrib>Ogiela, Christopher</creatorcontrib><creatorcontrib>Reilly, Regina M</creatorcontrib><creatorcontrib>Campbell, Thomas J</creatorcontrib><creatorcontrib>Polakowski, James S</creatorcontrib><creatorcontrib>Hernandez, Lisa</creatorcontrib><creatorcontrib>Marsh, Kennan C</creatorcontrib><creatorcontrib>Shapiro, Robin</creatorcontrib><creatorcontrib>Knourek-Segel, Victoria</creatorcontrib><creatorcontrib>Droz, Brian</creatorcontrib><creatorcontrib>Bush, Eugene</creatorcontrib><creatorcontrib>Brune, Michael</creatorcontrib><creatorcontrib>Preusser, Lee C</creatorcontrib><creatorcontrib>Fryer, Ryan M</creatorcontrib><creatorcontrib>Reinhart, Glenn A</creatorcontrib><creatorcontrib>Houseman, Kathryn</creatorcontrib><creatorcontrib>Diaz, Gilbert</creatorcontrib><creatorcontrib>Mikhail, Ann</creatorcontrib><creatorcontrib>Limberis, James T</creatorcontrib><creatorcontrib>Sham, Hing L</creatorcontrib><creatorcontrib>Collins, Christine A</creatorcontrib><creatorcontrib>Kym, Philip R</creatorcontrib><title>Optimization of Chromone-2-carboxamide Melanin Concentrating Hormone Receptor 1 Antagonists: Assessment of Potency, Efficacy, and Cardiovascular Safety</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Evaluation of multiple structurally distinct series of melanin concentrating hormone receptor 1 antagonists in an anesthetized rat cardiovascualar assay led to the identification of a chromone-2-carboxamide series as having excellent safety against the chosen cardiovascular endpoints at high drug concentrations in the plasma and brain. Optimization of this series led to considerable improvements in affinity, functional potency, and pharmacokinetic profile. This led to the identification of a 7-fluorochromone-2-carboxamide (22) that was orally efficacious in a diet-induced obese mouse model, retained a favorable cardiovascular profile in rat, and demonstrated dramatic improvement in effects on mean arterial pressure in our dog cardiovascular model compared to other series reported by our group. However, this analogue also led to prolongation of the QT interval in the dog that was linked to affinity for hERG channel and unexpectedly potent functional blockade of this ion channel.</description><subject>Acylation</subject><subject>Animals</subject><subject>Area Under Curve</subject><subject>Benzodioxoles - pharmacokinetics</subject><subject>Benzodioxoles - pharmacology</subject><subject>Benzodioxoles - toxicity</subject><subject>Biological and medical sciences</subject><subject>Blood Pressure - drug effects</subject><subject>Body Weight - drug effects</subject><subject>Calcium - metabolism</subject><subject>Cardiovascular Diseases - chemically induced</subject><subject>Cell Line</subject><subject>Chromones - pharmacokinetics</subject><subject>Chromones - pharmacology</subject><subject>Chromones - toxicity</subject><subject>Dogs</subject><subject>Electrocardiography - drug effects</subject><subject>Female</subject><subject>Half-Life</subject><subject>Heart Rate - drug effects</subject><subject>Hormones. Endocrine system</subject><subject>Indicators and Reagents</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Pharmacology. Drug treatments</subject><subject>Potassium Channels - drug effects</subject><subject>Potassium Channels - metabolism</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, Somatostatin - antagonists & inhibitors</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0MGO0zAQBmALgdiycOAFkC8cViIwEydOwq2KFhap1S60Am7WxHEWl8au7BRtOXHlFXg8noRUrbYXTrbkz7_HP2PPEV4jpPhm1YMEWQrzgE0wTyHJSsgesglAmiapTMUZexLjCgAEpuIxO8MCZAZFPmF_rjeD7e1PGqx33He8_hZ8751J0kRTaPwd9bY1fG7W5KzjtXfauCGM3t3yKx_2ln8y2mwGHzjyqRvo1jsbh_j276_ffBqjibEf7-zTb_xgnN694pddZzXtd-RaXlNorf9BUW_XFPiCOjPsnrJHHa2jeXZcz9ny3eWyvkpm1-8_1NNZQqLEIalMVSFmutGywQ5llbXY5KbBqpJUgC6EbEUDaCrITS7bDAmrLCcpxlcAxTm7OMTq4GMMplObYHsKO4Wg9vWq-3pH--JgN9umN-1JHvscwcsjGP9C6y6Q0zaeXJmKAgSMLjm4sSdzd39O4buShShytbxZqNl88XX-5WOpPp9ySUe18tvgxkb-M-A_FUSglA</recordid><startdate>20061102</startdate><enddate>20061102</enddate><creator>Lynch, John K</creator><creator>Freeman, Jennifer C</creator><creator>Judd, Andrew S</creator><creator>Iyengar, Rajesh</creator><creator>Mulhern, Mathew</creator><creator>Zhao, Gang</creator><creator>Napier, James J</creator><creator>Wodka, Dariusz</creator><creator>Brodjian, Sevan</creator><creator>Dayton, Brian D</creator><creator>Falls, Doug</creator><creator>Ogiela, Christopher</creator><creator>Reilly, Regina M</creator><creator>Campbell, Thomas J</creator><creator>Polakowski, James S</creator><creator>Hernandez, Lisa</creator><creator>Marsh, Kennan C</creator><creator>Shapiro, Robin</creator><creator>Knourek-Segel, Victoria</creator><creator>Droz, Brian</creator><creator>Bush, Eugene</creator><creator>Brune, Michael</creator><creator>Preusser, Lee C</creator><creator>Fryer, Ryan M</creator><creator>Reinhart, Glenn A</creator><creator>Houseman, Kathryn</creator><creator>Diaz, Gilbert</creator><creator>Mikhail, Ann</creator><creator>Limberis, James T</creator><creator>Sham, Hing L</creator><creator>Collins, Christine A</creator><creator>Kym, Philip R</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>IQODW</scope><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>20061102</creationdate><title>Optimization of Chromone-2-carboxamide Melanin Concentrating Hormone Receptor 1 Antagonists: Assessment of Potency, Efficacy, and Cardiovascular Safety</title><author>Lynch, John K ; Freeman, Jennifer C ; Judd, Andrew S ; Iyengar, Rajesh ; Mulhern, Mathew ; Zhao, Gang ; Napier, James J ; Wodka, Dariusz ; Brodjian, Sevan ; Dayton, Brian D ; Falls, Doug ; Ogiela, Christopher ; Reilly, Regina M ; Campbell, Thomas J ; Polakowski, James S ; Hernandez, Lisa ; Marsh, Kennan C ; Shapiro, Robin ; Knourek-Segel, Victoria ; Droz, Brian ; Bush, Eugene ; Brune, Michael ; Preusser, Lee C ; Fryer, Ryan M ; Reinhart, Glenn A ; Houseman, Kathryn ; Diaz, Gilbert ; Mikhail, Ann ; Limberis, James T ; Sham, Hing L ; Collins, Christine A ; Kym, Philip R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a381t-9e99114cbc6b1f1694d1b5eb1996a70c736d3b01e905e56d41a1945a63afe013</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Acylation</topic><topic>Animals</topic><topic>Area Under Curve</topic><topic>Benzodioxoles - pharmacokinetics</topic><topic>Benzodioxoles - pharmacology</topic><topic>Benzodioxoles - toxicity</topic><topic>Biological and medical sciences</topic><topic>Blood Pressure - drug effects</topic><topic>Body Weight - drug effects</topic><topic>Calcium - metabolism</topic><topic>Cardiovascular Diseases - chemically induced</topic><topic>Cell Line</topic><topic>Chromones - pharmacokinetics</topic><topic>Chromones - pharmacology</topic><topic>Chromones - toxicity</topic><topic>Dogs</topic><topic>Electrocardiography - drug effects</topic><topic>Female</topic><topic>Half-Life</topic><topic>Heart Rate - drug effects</topic><topic>Hormones. Endocrine system</topic><topic>Indicators and Reagents</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Pharmacology. Drug treatments</topic><topic>Potassium Channels - drug effects</topic><topic>Potassium Channels - metabolism</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptors, Somatostatin - antagonists & inhibitors</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lynch, John K</creatorcontrib><creatorcontrib>Freeman, Jennifer C</creatorcontrib><creatorcontrib>Judd, Andrew S</creatorcontrib><creatorcontrib>Iyengar, Rajesh</creatorcontrib><creatorcontrib>Mulhern, Mathew</creatorcontrib><creatorcontrib>Zhao, Gang</creatorcontrib><creatorcontrib>Napier, James J</creatorcontrib><creatorcontrib>Wodka, Dariusz</creatorcontrib><creatorcontrib>Brodjian, Sevan</creatorcontrib><creatorcontrib>Dayton, Brian D</creatorcontrib><creatorcontrib>Falls, Doug</creatorcontrib><creatorcontrib>Ogiela, Christopher</creatorcontrib><creatorcontrib>Reilly, Regina M</creatorcontrib><creatorcontrib>Campbell, Thomas J</creatorcontrib><creatorcontrib>Polakowski, James S</creatorcontrib><creatorcontrib>Hernandez, Lisa</creatorcontrib><creatorcontrib>Marsh, Kennan C</creatorcontrib><creatorcontrib>Shapiro, Robin</creatorcontrib><creatorcontrib>Knourek-Segel, Victoria</creatorcontrib><creatorcontrib>Droz, Brian</creatorcontrib><creatorcontrib>Bush, Eugene</creatorcontrib><creatorcontrib>Brune, Michael</creatorcontrib><creatorcontrib>Preusser, Lee C</creatorcontrib><creatorcontrib>Fryer, Ryan M</creatorcontrib><creatorcontrib>Reinhart, Glenn A</creatorcontrib><creatorcontrib>Houseman, Kathryn</creatorcontrib><creatorcontrib>Diaz, Gilbert</creatorcontrib><creatorcontrib>Mikhail, Ann</creatorcontrib><creatorcontrib>Limberis, James T</creatorcontrib><creatorcontrib>Sham, Hing L</creatorcontrib><creatorcontrib>Collins, Christine A</creatorcontrib><creatorcontrib>Kym, Philip R</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lynch, John K</au><au>Freeman, Jennifer C</au><au>Judd, Andrew S</au><au>Iyengar, Rajesh</au><au>Mulhern, Mathew</au><au>Zhao, Gang</au><au>Napier, James J</au><au>Wodka, Dariusz</au><au>Brodjian, Sevan</au><au>Dayton, Brian D</au><au>Falls, Doug</au><au>Ogiela, Christopher</au><au>Reilly, Regina M</au><au>Campbell, Thomas J</au><au>Polakowski, James S</au><au>Hernandez, Lisa</au><au>Marsh, Kennan C</au><au>Shapiro, Robin</au><au>Knourek-Segel, Victoria</au><au>Droz, Brian</au><au>Bush, Eugene</au><au>Brune, Michael</au><au>Preusser, Lee C</au><au>Fryer, Ryan M</au><au>Reinhart, Glenn A</au><au>Houseman, Kathryn</au><au>Diaz, Gilbert</au><au>Mikhail, Ann</au><au>Limberis, James T</au><au>Sham, Hing L</au><au>Collins, Christine A</au><au>Kym, Philip R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Optimization of Chromone-2-carboxamide Melanin Concentrating Hormone Receptor 1 Antagonists: Assessment of Potency, Efficacy, and Cardiovascular Safety</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2006-11-02</date><risdate>2006</risdate><volume>49</volume><issue>22</issue><spage>6569</spage><epage>6584</epage><pages>6569-6584</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Evaluation of multiple structurally distinct series of melanin concentrating hormone receptor 1 antagonists in an anesthetized rat cardiovascualar assay led to the identification of a chromone-2-carboxamide series as having excellent safety against the chosen cardiovascular endpoints at high drug concentrations in the plasma and brain. Optimization of this series led to considerable improvements in affinity, functional potency, and pharmacokinetic profile. This led to the identification of a 7-fluorochromone-2-carboxamide (22) that was orally efficacious in a diet-induced obese mouse model, retained a favorable cardiovascular profile in rat, and demonstrated dramatic improvement in effects on mean arterial pressure in our dog cardiovascular model compared to other series reported by our group. However, this analogue also led to prolongation of the QT interval in the dog that was linked to affinity for hERG channel and unexpectedly potent functional blockade of this ion channel.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>17064075</pmid><doi>10.1021/jm060683e</doi><tpages>16</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2006-11, Vol.49 (22), p.6569-6584 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_crossref_primary_10_1021_jm060683e |
| source | ACS Publications; MEDLINE |
| subjects | Acylation Animals Area Under Curve Benzodioxoles - pharmacokinetics Benzodioxoles - pharmacology Benzodioxoles - toxicity Biological and medical sciences Blood Pressure - drug effects Body Weight - drug effects Calcium - metabolism Cardiovascular Diseases - chemically induced Cell Line Chromones - pharmacokinetics Chromones - pharmacology Chromones - toxicity Dogs Electrocardiography - drug effects Female Half-Life Heart Rate - drug effects Hormones. Endocrine system Indicators and Reagents Medical sciences Mice Mice, Inbred C57BL Pharmacology. Drug treatments Potassium Channels - drug effects Potassium Channels - metabolism Rats Rats, Sprague-Dawley Receptors, Somatostatin - antagonists & inhibitors Structure-Activity Relationship |
| title | Optimization of Chromone-2-carboxamide Melanin Concentrating Hormone Receptor 1 Antagonists: Assessment of Potency, Efficacy, and Cardiovascular Safety |
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