Synthesis and cardiotonic activity of novel biimidazoles
A series of substituted 2,2'-bi-1H-imidazoles and related analogues was synthesized and evaluated for inotropic activity. Structure-activity relationship studies based on a nonclassical bioisosteric approach indicated the necessity of a cyano group on one of the imidazole rings to obtain the de...
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| Veröffentlicht in: | Journal of medicinal chemistry 1990-01, Vol.33 (1), p.317-327 |
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| container_title | Journal of medicinal chemistry |
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| creator | Matthews, Donald P McCarthy, James R Whitten, Jeffrey P Kastner, Philip R Barney, Charlotte L Marshall, Franklin N Ertel, Marcia A Burkhard, Therese Shea, Philip J Kariya, Takashi |
| description | A series of substituted 2,2'-bi-1H-imidazoles and related analogues was synthesized and evaluated for inotropic activity. Structure-activity relationship studies based on a nonclassical bioisosteric approach indicated the necessity of a cyano group on one of the imidazole rings to obtain the desired pharmacological profile. 4(5)-Cyano-2,2'-bi-1H-imidazole (15a) was the most potent inotropic agent in the series. It produced a 25% increase in left ventricular dP/dt at 0.16 mg/kg iv (ED25% = 0.16 mg/kg) and increased left ventricular contractile force 60% at 1 mg/kg iv in anesthetized dogs. Compound 15a is a good inhibitor of type IV cyclic nucleotide phosphodiesterase isolated from dog heart having a potency similar to that of amrinone. Neither 5'-cyano-2,4'-bi-1H-imidazole (44) nor 4-cyano-2,4'-bi-1H-imidazole (48) demonstrated inotropic activity. In addition, the two possible 1,1'-dimethylcyano-2,2'-bi-1H-imidazoles (24 and 25) were inactive, indicating that an acidic NH as well as a cyano group are essential for inotropic activity. |
| doi_str_mv | 10.1021/jm00163a052 |
| format | Article |
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Structure-activity relationship studies based on a nonclassical bioisosteric approach indicated the necessity of a cyano group on one of the imidazole rings to obtain the desired pharmacological profile. 4(5)-Cyano-2,2'-bi-1H-imidazole (15a) was the most potent inotropic agent in the series. It produced a 25% increase in left ventricular dP/dt at 0.16 mg/kg iv (ED25% = 0.16 mg/kg) and increased left ventricular contractile force 60% at 1 mg/kg iv in anesthetized dogs. Compound 15a is a good inhibitor of type IV cyclic nucleotide phosphodiesterase isolated from dog heart having a potency similar to that of amrinone. Neither 5'-cyano-2,4'-bi-1H-imidazole (44) nor 4-cyano-2,4'-bi-1H-imidazole (48) demonstrated inotropic activity. In addition, the two possible 1,1'-dimethylcyano-2,2'-bi-1H-imidazoles (24 and 25) were inactive, indicating that an acidic NH as well as a cyano group are essential for inotropic activity.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00163a052</identifier><identifier>PMID: 2153209</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>2',3'-Cyclic-Nucleotide Phosphodiesterases - antagonists & inhibitors ; Amrinone - pharmacology ; Animals ; Blood Pressure - drug effects ; Cardiotonic Agents ; Chemical Phenomena ; Chemistry ; Dogs ; Exact sciences and technology ; Furans - chemical synthesis ; Furans - pharmacology ; Heart Rate - drug effects ; Heterocyclic compounds ; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings ; Imidazoles - chemical synthesis ; Imidazoles - pharmacology ; inotropism ; Isoenzymes - antagonists & inhibitors ; Milrinone ; Molecular Structure ; Myocardial Contraction - drug effects ; Organic chemistry ; Preparations and properties ; Pyridones - pharmacology ; Rats ; Stimulation, Chemical ; Structure-Activity Relationship ; Thiazoles - chemical synthesis ; Thiazoles - pharmacology ; Thiophenes - chemical synthesis ; Thiophenes - pharmacology</subject><ispartof>Journal of medicinal chemistry, 1990-01, Vol.33 (1), p.317-327</ispartof><rights>1990 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a480t-55f9014eb4e6e8c9a60473a45acdd0763ce695dbe52b617d79d7d70a8bd474c73</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm00163a052$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00163a052$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2751,4009,27055,27902,27903,27904,56717,56767</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=6757605$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/2153209$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Matthews, Donald P</creatorcontrib><creatorcontrib>McCarthy, James R</creatorcontrib><creatorcontrib>Whitten, Jeffrey P</creatorcontrib><creatorcontrib>Kastner, Philip R</creatorcontrib><creatorcontrib>Barney, Charlotte L</creatorcontrib><creatorcontrib>Marshall, Franklin N</creatorcontrib><creatorcontrib>Ertel, Marcia A</creatorcontrib><creatorcontrib>Burkhard, Therese</creatorcontrib><creatorcontrib>Shea, Philip J</creatorcontrib><creatorcontrib>Kariya, Takashi</creatorcontrib><title>Synthesis and cardiotonic activity of novel biimidazoles</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A series of substituted 2,2'-bi-1H-imidazoles and related analogues was synthesized and evaluated for inotropic activity. Structure-activity relationship studies based on a nonclassical bioisosteric approach indicated the necessity of a cyano group on one of the imidazole rings to obtain the desired pharmacological profile. 4(5)-Cyano-2,2'-bi-1H-imidazole (15a) was the most potent inotropic agent in the series. It produced a 25% increase in left ventricular dP/dt at 0.16 mg/kg iv (ED25% = 0.16 mg/kg) and increased left ventricular contractile force 60% at 1 mg/kg iv in anesthetized dogs. Compound 15a is a good inhibitor of type IV cyclic nucleotide phosphodiesterase isolated from dog heart having a potency similar to that of amrinone. Neither 5'-cyano-2,4'-bi-1H-imidazole (44) nor 4-cyano-2,4'-bi-1H-imidazole (48) demonstrated inotropic activity. In addition, the two possible 1,1'-dimethylcyano-2,2'-bi-1H-imidazoles (24 and 25) were inactive, indicating that an acidic NH as well as a cyano group are essential for inotropic activity.</description><subject>2',3'-Cyclic-Nucleotide Phosphodiesterases - antagonists & inhibitors</subject><subject>Amrinone - pharmacology</subject><subject>Animals</subject><subject>Blood Pressure - drug effects</subject><subject>Cardiotonic Agents</subject><subject>Chemical Phenomena</subject><subject>Chemistry</subject><subject>Dogs</subject><subject>Exact sciences and technology</subject><subject>Furans - chemical synthesis</subject><subject>Furans - pharmacology</subject><subject>Heart Rate - drug effects</subject><subject>Heterocyclic compounds</subject><subject>Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings</subject><subject>Imidazoles - chemical synthesis</subject><subject>Imidazoles - pharmacology</subject><subject>inotropism</subject><subject>Isoenzymes - antagonists & inhibitors</subject><subject>Milrinone</subject><subject>Molecular Structure</subject><subject>Myocardial Contraction - drug effects</subject><subject>Organic chemistry</subject><subject>Preparations and properties</subject><subject>Pyridones - pharmacology</subject><subject>Rats</subject><subject>Stimulation, Chemical</subject><subject>Structure-Activity Relationship</subject><subject>Thiazoles - chemical synthesis</subject><subject>Thiazoles - pharmacology</subject><subject>Thiophenes - chemical synthesis</subject><subject>Thiophenes - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1990</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0Etr3DAUBWARWtLJY5V1wYvSLIKTq7e9LEPzoIEGkkDIRlxLMtHUtlLJEzL99XWYYcii0I20OB-XwyHkiMIpBUbPFj0AVRxBsh0yo5JBKSoQH8gMgLGSKcY_kb2cFwDAKeO7ZJdRyRnUM1LdrobxyeeQCxxcYTG5EMc4BFugHcNLGFdFbIshvviuaELog8M_sfP5gHxsscv-cPPvk_vz73fzy_L658XV_Nt1iVOHsZSyrYEK3wivfGVrVCA0RyHROgdacetVLV3jJWsU1U7XbnoAq8YJLazm--Tr-u5zir-XPo-mD9n6rsPBx2U2upa8Vkr-F1IpFBegJniyhjbFnJNvzXMKPaaVoWDeBjXvBp30583ZZdN7t7WbBaf8yybHbLFrEw425C1TWmoFb-3KNQt59K_bGNOviXAtzd3Nrbl8fJjfiEqbH5M_Xnu02SziMg3TyP8s-BcW1Zfh</recordid><startdate>19900101</startdate><enddate>19900101</enddate><creator>Matthews, Donald P</creator><creator>McCarthy, James R</creator><creator>Whitten, Jeffrey P</creator><creator>Kastner, Philip R</creator><creator>Barney, Charlotte L</creator><creator>Marshall, Franklin N</creator><creator>Ertel, Marcia A</creator><creator>Burkhard, Therese</creator><creator>Shea, Philip J</creator><creator>Kariya, Takashi</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>8FD</scope><scope>FR3</scope><scope>M7Z</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>19900101</creationdate><title>Synthesis and cardiotonic activity of novel biimidazoles</title><author>Matthews, Donald P ; McCarthy, James R ; Whitten, Jeffrey P ; Kastner, Philip R ; Barney, Charlotte L ; Marshall, Franklin N ; Ertel, Marcia A ; Burkhard, Therese ; Shea, Philip J ; Kariya, Takashi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a480t-55f9014eb4e6e8c9a60473a45acdd0763ce695dbe52b617d79d7d70a8bd474c73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1990</creationdate><topic>2',3'-Cyclic-Nucleotide Phosphodiesterases - antagonists & inhibitors</topic><topic>Amrinone - pharmacology</topic><topic>Animals</topic><topic>Blood Pressure - drug effects</topic><topic>Cardiotonic Agents</topic><topic>Chemical Phenomena</topic><topic>Chemistry</topic><topic>Dogs</topic><topic>Exact sciences and technology</topic><topic>Furans - chemical synthesis</topic><topic>Furans - pharmacology</topic><topic>Heart Rate - drug effects</topic><topic>Heterocyclic compounds</topic><topic>Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings</topic><topic>Imidazoles - chemical synthesis</topic><topic>Imidazoles - pharmacology</topic><topic>inotropism</topic><topic>Isoenzymes - antagonists & inhibitors</topic><topic>Milrinone</topic><topic>Molecular Structure</topic><topic>Myocardial Contraction - drug effects</topic><topic>Organic chemistry</topic><topic>Preparations and properties</topic><topic>Pyridones - pharmacology</topic><topic>Rats</topic><topic>Stimulation, Chemical</topic><topic>Structure-Activity Relationship</topic><topic>Thiazoles - chemical synthesis</topic><topic>Thiazoles - pharmacology</topic><topic>Thiophenes - chemical synthesis</topic><topic>Thiophenes - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Matthews, Donald P</creatorcontrib><creatorcontrib>McCarthy, James R</creatorcontrib><creatorcontrib>Whitten, Jeffrey P</creatorcontrib><creatorcontrib>Kastner, Philip R</creatorcontrib><creatorcontrib>Barney, Charlotte L</creatorcontrib><creatorcontrib>Marshall, Franklin N</creatorcontrib><creatorcontrib>Ertel, Marcia A</creatorcontrib><creatorcontrib>Burkhard, Therese</creatorcontrib><creatorcontrib>Shea, Philip J</creatorcontrib><creatorcontrib>Kariya, Takashi</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><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biochemistry Abstracts 1</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Matthews, Donald P</au><au>McCarthy, James R</au><au>Whitten, Jeffrey P</au><au>Kastner, Philip R</au><au>Barney, Charlotte L</au><au>Marshall, Franklin N</au><au>Ertel, Marcia A</au><au>Burkhard, Therese</au><au>Shea, Philip J</au><au>Kariya, Takashi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and cardiotonic activity of novel biimidazoles</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1990-01-01</date><risdate>1990</risdate><volume>33</volume><issue>1</issue><spage>317</spage><epage>327</epage><pages>317-327</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>A series of substituted 2,2'-bi-1H-imidazoles and related analogues was synthesized and evaluated for inotropic activity. Structure-activity relationship studies based on a nonclassical bioisosteric approach indicated the necessity of a cyano group on one of the imidazole rings to obtain the desired pharmacological profile. 4(5)-Cyano-2,2'-bi-1H-imidazole (15a) was the most potent inotropic agent in the series. It produced a 25% increase in left ventricular dP/dt at 0.16 mg/kg iv (ED25% = 0.16 mg/kg) and increased left ventricular contractile force 60% at 1 mg/kg iv in anesthetized dogs. Compound 15a is a good inhibitor of type IV cyclic nucleotide phosphodiesterase isolated from dog heart having a potency similar to that of amrinone. Neither 5'-cyano-2,4'-bi-1H-imidazole (44) nor 4-cyano-2,4'-bi-1H-imidazole (48) demonstrated inotropic activity. In addition, the two possible 1,1'-dimethylcyano-2,2'-bi-1H-imidazoles (24 and 25) were inactive, indicating that an acidic NH as well as a cyano group are essential for inotropic activity.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>2153209</pmid><doi>10.1021/jm00163a052</doi><tpages>11</tpages></addata></record> |
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| subjects | 2',3'-Cyclic-Nucleotide Phosphodiesterases - antagonists & inhibitors Amrinone - pharmacology Animals Blood Pressure - drug effects Cardiotonic Agents Chemical Phenomena Chemistry Dogs Exact sciences and technology Furans - chemical synthesis Furans - pharmacology Heart Rate - drug effects Heterocyclic compounds Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings Imidazoles - chemical synthesis Imidazoles - pharmacology inotropism Isoenzymes - antagonists & inhibitors Milrinone Molecular Structure Myocardial Contraction - drug effects Organic chemistry Preparations and properties Pyridones - pharmacology Rats Stimulation, Chemical Structure-Activity Relationship Thiazoles - chemical synthesis Thiazoles - pharmacology Thiophenes - chemical synthesis Thiophenes - pharmacology |
| title | Synthesis and cardiotonic activity of novel biimidazoles |
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