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Design and Synthesis of Tricyclic Imidazo[4,5-b]pyridin-2-ones as Corticotropin-Releasing Factor-1 Antagonists
The synthesis and SAR studies of tricyclic imidazo[4,5-b]pyridin-2-ones as human corticotropin-releasing factor receptor (CRF1) antagonists are discussed herein. Compound 16g was identified as a functional antagonist that inhibited CRF-stimulated cyclic adenosine monophosphate production and CRF-ind...
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| Published in: | Journal of medicinal chemistry 2005-08, Vol.48 (16), p.5104-5107 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| container_end_page | 5107 |
| container_issue | 16 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 48 |
| creator | Guo, Zhiqiang Tellew, John E Gross, Raymond S Dyck, Brian Grey, Jonathan Haddach, Mustapha Kiankarimi, Mehrak Lanier, Marion Li, Bin-Feng Luo, Zhiyong McCarthy, James R Moorjani, Manisha Saunders, John Sullivan, Robert Zhang, Xiaohu Zamani-Kord, Said Grigoriadis, Dimitri E Crowe, Paul D Chen, Ta Kung Williams, John P |
| description | The synthesis and SAR studies of tricyclic imidazo[4,5-b]pyridin-2-ones as human corticotropin-releasing factor receptor (CRF1) antagonists are discussed herein. Compound 16g was identified as a functional antagonist that inhibited CRF-stimulated cyclic adenosine monophosphate production and CRF-induced adrenocorticotrophic hormone release. Pharmacokinetics studies in rats showed that 16g was orally bioavailable, had good brain penetration, and had a moderate half-life. In our effort to identify CRF1 antagonists with improved pharmacokinetics properties, 16g exhibited a favorably lower volume of distribution. |
| doi_str_mv | 10.1021/jm050384+ |
| format | article |
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Compound 16g was identified as a functional antagonist that inhibited CRF-stimulated cyclic adenosine monophosphate production and CRF-induced adrenocorticotrophic hormone release. Pharmacokinetics studies in rats showed that 16g was orally bioavailable, had good brain penetration, and had a moderate half-life. In our effort to identify CRF1 antagonists with improved pharmacokinetics properties, 16g exhibited a favorably lower volume of distribution.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm050384+</identifier><identifier>PMID: 16078829</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Administration, Oral ; Adrenocorticotropic Hormone - blood ; Animals ; Biological and medical sciences ; Blood-Brain Barrier - metabolism ; CHO Cells ; Corticotropin-Releasing Hormone - pharmacology ; Cricetinae ; Cricetulus ; Cyclic AMP - antagonists & inhibitors ; Cyclic AMP - biosynthesis ; Drug Design ; Heterocyclic Compounds, 3-Ring - chemical synthesis ; Heterocyclic Compounds, 3-Ring - pharmacokinetics ; Heterocyclic Compounds, 3-Ring - pharmacology ; Hormones. Endocrine system ; Humans ; Imidazoles - chemical synthesis ; Imidazoles - pharmacokinetics ; Imidazoles - pharmacology ; Injections, Intravenous ; Male ; Medical sciences ; Pharmacology. Drug treatments ; Pyridines - chemical synthesis ; Pyridines - pharmacokinetics ; Pyridines - pharmacology ; Radioligand Assay ; Rats ; Rats, Sprague-Dawley ; Receptors, Corticotropin-Releasing Hormone - antagonists & inhibitors ; Stereoisomerism ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2005-08, Vol.48 (16), p.5104-5107</ispartof><rights>Copyright © 2005 American Chemical Society</rights><rights>2005 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a378t-531fb087452a637d9bb147816ccda2f31d5b0e96c41ab8568f4f37da60d508403</citedby><cites>FETCH-LOGICAL-a378t-531fb087452a637d9bb147816ccda2f31d5b0e96c41ab8568f4f37da60d508403</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17021591$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16078829$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Guo, Zhiqiang</creatorcontrib><creatorcontrib>Tellew, John E</creatorcontrib><creatorcontrib>Gross, Raymond S</creatorcontrib><creatorcontrib>Dyck, Brian</creatorcontrib><creatorcontrib>Grey, Jonathan</creatorcontrib><creatorcontrib>Haddach, Mustapha</creatorcontrib><creatorcontrib>Kiankarimi, Mehrak</creatorcontrib><creatorcontrib>Lanier, Marion</creatorcontrib><creatorcontrib>Li, Bin-Feng</creatorcontrib><creatorcontrib>Luo, Zhiyong</creatorcontrib><creatorcontrib>McCarthy, James R</creatorcontrib><creatorcontrib>Moorjani, Manisha</creatorcontrib><creatorcontrib>Saunders, John</creatorcontrib><creatorcontrib>Sullivan, Robert</creatorcontrib><creatorcontrib>Zhang, Xiaohu</creatorcontrib><creatorcontrib>Zamani-Kord, Said</creatorcontrib><creatorcontrib>Grigoriadis, Dimitri E</creatorcontrib><creatorcontrib>Crowe, Paul D</creatorcontrib><creatorcontrib>Chen, Ta Kung</creatorcontrib><creatorcontrib>Williams, John P</creatorcontrib><title>Design and Synthesis of Tricyclic Imidazo[4,5-b]pyridin-2-ones as Corticotropin-Releasing Factor-1 Antagonists</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The synthesis and SAR studies of tricyclic imidazo[4,5-b]pyridin-2-ones as human corticotropin-releasing factor receptor (CRF1) antagonists are discussed herein. Compound 16g was identified as a functional antagonist that inhibited CRF-stimulated cyclic adenosine monophosphate production and CRF-induced adrenocorticotrophic hormone release. Pharmacokinetics studies in rats showed that 16g was orally bioavailable, had good brain penetration, and had a moderate half-life. In our effort to identify CRF1 antagonists with improved pharmacokinetics properties, 16g exhibited a favorably lower volume of distribution.</description><subject>Administration, Oral</subject><subject>Adrenocorticotropic Hormone - blood</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Blood-Brain Barrier - metabolism</subject><subject>CHO Cells</subject><subject>Corticotropin-Releasing Hormone - pharmacology</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>Cyclic AMP - antagonists & inhibitors</subject><subject>Cyclic AMP - biosynthesis</subject><subject>Drug Design</subject><subject>Heterocyclic Compounds, 3-Ring - chemical synthesis</subject><subject>Heterocyclic Compounds, 3-Ring - pharmacokinetics</subject><subject>Heterocyclic Compounds, 3-Ring - pharmacology</subject><subject>Hormones. Endocrine system</subject><subject>Humans</subject><subject>Imidazoles - chemical synthesis</subject><subject>Imidazoles - pharmacokinetics</subject><subject>Imidazoles - pharmacology</subject><subject>Injections, Intravenous</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Pharmacology. Drug treatments</subject><subject>Pyridines - chemical synthesis</subject><subject>Pyridines - pharmacokinetics</subject><subject>Pyridines - pharmacology</subject><subject>Radioligand Assay</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, Corticotropin-Releasing Hormone - antagonists & inhibitors</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><recordid>eNpl0F1rFDEUBuAgil2rF_4BmQuVgkbzPZnLdttqsWCxqxREwplMZs12JlmTWXD99UZ2tRdehZPz8HJ4EXpKyRtKGH27GokkXItX99CMSkaw0ETcRzNCGMNMMX6AHuW8IoRwyvhDdEAVqbVmzQyFU5f9MlQQuup6G6bvZcxV7KtF8nZrB2-ri9F38Ct-Fa8lbr-tt8l3PmCGY3C5glzNY5q8jVOK6_L_yQ0Osg_L6hzsFBOm1XGYYBmDz1N-jB70MGT3ZP8eos_nZ4v5e3z58d3F_PgSA6_1hCWnfUt0LSQDxeuuaVsqak2VtR2wntNOtsQ1ygoKrZZK96IvDBTpJNGC8EP0cpe7TvHHxuXJjD5bNwwQXNxko7QQqiZNgUc7aFPMObnerJMfIW0NJeZPueZvuYU-22du2tF1d3BfZgEv9gCyhaFPEKzPd64ucbKhxeGdK424n__2kG6NqnktzeLq2px8kacfbk5uzFXxz3cebDaruEmhVPf_fb8BEt2bWg</recordid><startdate>20050811</startdate><enddate>20050811</enddate><creator>Guo, Zhiqiang</creator><creator>Tellew, John E</creator><creator>Gross, Raymond S</creator><creator>Dyck, Brian</creator><creator>Grey, Jonathan</creator><creator>Haddach, Mustapha</creator><creator>Kiankarimi, Mehrak</creator><creator>Lanier, Marion</creator><creator>Li, Bin-Feng</creator><creator>Luo, Zhiyong</creator><creator>McCarthy, James R</creator><creator>Moorjani, Manisha</creator><creator>Saunders, John</creator><creator>Sullivan, Robert</creator><creator>Zhang, Xiaohu</creator><creator>Zamani-Kord, Said</creator><creator>Grigoriadis, Dimitri E</creator><creator>Crowe, Paul D</creator><creator>Chen, Ta Kung</creator><creator>Williams, John P</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><scope>7X8</scope></search><sort><creationdate>20050811</creationdate><title>Design and Synthesis of Tricyclic Imidazo[4,5-b]pyridin-2-ones as Corticotropin-Releasing Factor-1 Antagonists</title><author>Guo, Zhiqiang ; Tellew, John E ; Gross, Raymond S ; Dyck, Brian ; Grey, Jonathan ; Haddach, Mustapha ; Kiankarimi, Mehrak ; Lanier, Marion ; Li, Bin-Feng ; Luo, Zhiyong ; McCarthy, James R ; Moorjani, Manisha ; Saunders, John ; Sullivan, Robert ; Zhang, Xiaohu ; Zamani-Kord, Said ; Grigoriadis, Dimitri E ; Crowe, Paul D ; Chen, Ta Kung ; Williams, John P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a378t-531fb087452a637d9bb147816ccda2f31d5b0e96c41ab8568f4f37da60d508403</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Administration, Oral</topic><topic>Adrenocorticotropic Hormone - blood</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Blood-Brain Barrier - metabolism</topic><topic>CHO Cells</topic><topic>Corticotropin-Releasing Hormone - pharmacology</topic><topic>Cricetinae</topic><topic>Cricetulus</topic><topic>Cyclic AMP - antagonists & inhibitors</topic><topic>Cyclic AMP - biosynthesis</topic><topic>Drug Design</topic><topic>Heterocyclic Compounds, 3-Ring - chemical synthesis</topic><topic>Heterocyclic Compounds, 3-Ring - pharmacokinetics</topic><topic>Heterocyclic Compounds, 3-Ring - pharmacology</topic><topic>Hormones. 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Med. Chem</addtitle><date>2005-08-11</date><risdate>2005</risdate><volume>48</volume><issue>16</issue><spage>5104</spage><epage>5107</epage><pages>5104-5107</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>The synthesis and SAR studies of tricyclic imidazo[4,5-b]pyridin-2-ones as human corticotropin-releasing factor receptor (CRF1) antagonists are discussed herein. Compound 16g was identified as a functional antagonist that inhibited CRF-stimulated cyclic adenosine monophosphate production and CRF-induced adrenocorticotrophic hormone release. Pharmacokinetics studies in rats showed that 16g was orally bioavailable, had good brain penetration, and had a moderate half-life. In our effort to identify CRF1 antagonists with improved pharmacokinetics properties, 16g exhibited a favorably lower volume of distribution.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>16078829</pmid><doi>10.1021/jm050384+</doi><tpages>4</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Journal of medicinal chemistry, 2005-08, Vol.48 (16), p.5104-5107 |
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| subjects | Administration, Oral Adrenocorticotropic Hormone - blood Animals Biological and medical sciences Blood-Brain Barrier - metabolism CHO Cells Corticotropin-Releasing Hormone - pharmacology Cricetinae Cricetulus Cyclic AMP - antagonists & inhibitors Cyclic AMP - biosynthesis Drug Design Heterocyclic Compounds, 3-Ring - chemical synthesis Heterocyclic Compounds, 3-Ring - pharmacokinetics Heterocyclic Compounds, 3-Ring - pharmacology Hormones. Endocrine system Humans Imidazoles - chemical synthesis Imidazoles - pharmacokinetics Imidazoles - pharmacology Injections, Intravenous Male Medical sciences Pharmacology. Drug treatments Pyridines - chemical synthesis Pyridines - pharmacokinetics Pyridines - pharmacology Radioligand Assay Rats Rats, Sprague-Dawley Receptors, Corticotropin-Releasing Hormone - antagonists & inhibitors Stereoisomerism Structure-Activity Relationship |
| title | Design and Synthesis of Tricyclic Imidazo[4,5-b]pyridin-2-ones as Corticotropin-Releasing Factor-1 Antagonists |
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