Benzazepinone calcium channel blockers. 4. Structure-activity overview and intracellular binding site
We have synthesized a series of benzazepinones (2) in order to determine the structure-activity relationships (SAR) for calcium channel blockers related to diltiazem. A prerequisite for calcium channel blocking activity in vitro and in vivo is the presence of two pharmacophores: a 4'-aryl methy...
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| Veröffentlicht in: | Journal of medicinal chemistry 1992-02, Vol.35 (4), p.780-793 |
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| container_end_page | 793 |
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| container_issue | 4 |
| container_start_page | 780 |
| container_title | Journal of medicinal chemistry |
| container_volume | 35 |
| creator | Kimball, S. David Floyd, David M Das, Jagabandhu Hunt, John T Krapcho, John Rovnyak, George Duff, Keith J Lee, Ving G Moquin, Robert V |
| description | We have synthesized a series of benzazepinones (2) in order to determine the structure-activity relationships (SAR) for calcium channel blockers related to diltiazem. A prerequisite for calcium channel blocking activity in vitro and in vivo is the presence of two pharmacophores: a 4'-aryl methyl ether and a basic substituent appended to N1 with a pKa in the physiological range. When these constraints are satisfied, a wide variety of substitution is tolerated at C6, C7, and C3. The presence of an electron-withdrawing group at C6 appears to enhance potency in vitro and in vivo. For such benzazepinones, activity is primarily dependent upon lipophilicity, as measured by log P. We believe these compounds must partition into the cell membrane in order to access their receptor. The quaternary methiodide 15k was used to demonstrate that the binding site for benzazepinones is on the intracellular face of the membrane. This work represents the first comprehensive SAR of diltiazem-like calcium channel blockers. |
| doi_str_mv | 10.1021/jm00082a020 |
| format | Article |
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Structure-activity overview and intracellular binding site</title><source>MEDLINE</source><source>American Chemical Society Journals</source><creator>Kimball, S. David ; Floyd, David M ; Das, Jagabandhu ; Hunt, John T ; Krapcho, John ; Rovnyak, George ; Duff, Keith J ; Lee, Ving G ; Moquin, Robert V</creator><creatorcontrib>Kimball, S. David ; Floyd, David M ; Das, Jagabandhu ; Hunt, John T ; Krapcho, John ; Rovnyak, George ; Duff, Keith J ; Lee, Ving G ; Moquin, Robert V</creatorcontrib><description>We have synthesized a series of benzazepinones (2) in order to determine the structure-activity relationships (SAR) for calcium channel blockers related to diltiazem. A prerequisite for calcium channel blocking activity in vitro and in vivo is the presence of two pharmacophores: a 4'-aryl methyl ether and a basic substituent appended to N1 with a pKa in the physiological range. When these constraints are satisfied, a wide variety of substitution is tolerated at C6, C7, and C3. The presence of an electron-withdrawing group at C6 appears to enhance potency in vitro and in vivo. For such benzazepinones, activity is primarily dependent upon lipophilicity, as measured by log P. We believe these compounds must partition into the cell membrane in order to access their receptor. The quaternary methiodide 15k was used to demonstrate that the binding site for benzazepinones is on the intracellular face of the membrane. This work represents the first comprehensive SAR of diltiazem-like calcium channel blockers.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00082a020</identifier><identifier>PMID: 1311765</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Benzazepines - chemistry ; Benzazepines - metabolism ; Binding Sites ; Calcium Channel Blockers - chemistry ; Calcium Channel Blockers - metabolism ; Calcium Channels - metabolism ; Cell Membrane - metabolism ; Chemical Phenomena ; Chemistry, Physical ; Diltiazem - analogs & derivatives ; Molecular Structure ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 1992-02, Vol.35 (4), p.780-793</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a354t-6bcfa171fd9d7700d8233c0439ac29d917598eaefd1a88ec40b2e6099c95ac713</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/jm00082a020$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00082a020$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/1311765$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kimball, S. David</creatorcontrib><creatorcontrib>Floyd, David M</creatorcontrib><creatorcontrib>Das, Jagabandhu</creatorcontrib><creatorcontrib>Hunt, John T</creatorcontrib><creatorcontrib>Krapcho, John</creatorcontrib><creatorcontrib>Rovnyak, George</creatorcontrib><creatorcontrib>Duff, Keith J</creatorcontrib><creatorcontrib>Lee, Ving G</creatorcontrib><creatorcontrib>Moquin, Robert V</creatorcontrib><title>Benzazepinone calcium channel blockers. 4. Structure-activity overview and intracellular binding site</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>We have synthesized a series of benzazepinones (2) in order to determine the structure-activity relationships (SAR) for calcium channel blockers related to diltiazem. A prerequisite for calcium channel blocking activity in vitro and in vivo is the presence of two pharmacophores: a 4'-aryl methyl ether and a basic substituent appended to N1 with a pKa in the physiological range. When these constraints are satisfied, a wide variety of substitution is tolerated at C6, C7, and C3. The presence of an electron-withdrawing group at C6 appears to enhance potency in vitro and in vivo. For such benzazepinones, activity is primarily dependent upon lipophilicity, as measured by log P. We believe these compounds must partition into the cell membrane in order to access their receptor. The quaternary methiodide 15k was used to demonstrate that the binding site for benzazepinones is on the intracellular face of the membrane. This work represents the first comprehensive SAR of diltiazem-like calcium channel blockers.</description><subject>Benzazepines - chemistry</subject><subject>Benzazepines - metabolism</subject><subject>Binding Sites</subject><subject>Calcium Channel Blockers - chemistry</subject><subject>Calcium Channel Blockers - metabolism</subject><subject>Calcium Channels - metabolism</subject><subject>Cell Membrane - metabolism</subject><subject>Chemical Phenomena</subject><subject>Chemistry, Physical</subject><subject>Diltiazem - analogs & derivatives</subject><subject>Molecular Structure</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1992</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkEtP3DAUhS3UCgbaVdeVvGoXKIMfSRwvCyoFgSgqVCytG-eGekicwXaGx69vUFDbRVd3cT6dc_UR8oGzJWeCH6x6xlglgAm2RRa8ECzLK5a_IQvGhMhEKeQO2Y1xNWGSC7lNtrnkXJXFguAh-md4xrXzg0dqobNu7Kn9Bd5jR-tusHcY4pLmS3qVwmjTGDADm9zGpSc6bDBsHD5Q8A11PgWw2HVjB4HWzjfO39LoEr4jb1voIr5_vXvk5_HX66OT7Pz7t9OjL-cZyCJPWVnbFrjibaMbpRhrKiGlZbnUYIVuNFeFrhCwbThUFdqc1QJLprXVBVjF5R75NPeuw3A_Ykymd_HlI_A4jNEoUclCl3IC92fQhiHGgK1ZB9dDeDKcmRep5h-pE_3xtXase2z-srPFKc_m3MWEj39iCHemVFIV5vryypxc6osfN2fcHE_855kHG81qGIOfpPx3-TevZo7M</recordid><startdate>19920201</startdate><enddate>19920201</enddate><creator>Kimball, S. 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David</creatorcontrib><creatorcontrib>Floyd, David M</creatorcontrib><creatorcontrib>Das, Jagabandhu</creatorcontrib><creatorcontrib>Hunt, John T</creatorcontrib><creatorcontrib>Krapcho, John</creatorcontrib><creatorcontrib>Rovnyak, George</creatorcontrib><creatorcontrib>Duff, Keith J</creatorcontrib><creatorcontrib>Lee, Ving G</creatorcontrib><creatorcontrib>Moquin, Robert V</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kimball, S. David</au><au>Floyd, David M</au><au>Das, Jagabandhu</au><au>Hunt, John T</au><au>Krapcho, John</au><au>Rovnyak, George</au><au>Duff, Keith J</au><au>Lee, Ving G</au><au>Moquin, Robert V</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Benzazepinone calcium channel blockers. 4. Structure-activity overview and intracellular binding site</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1992-02-01</date><risdate>1992</risdate><volume>35</volume><issue>4</issue><spage>780</spage><epage>793</epage><pages>780-793</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>We have synthesized a series of benzazepinones (2) in order to determine the structure-activity relationships (SAR) for calcium channel blockers related to diltiazem. A prerequisite for calcium channel blocking activity in vitro and in vivo is the presence of two pharmacophores: a 4'-aryl methyl ether and a basic substituent appended to N1 with a pKa in the physiological range. When these constraints are satisfied, a wide variety of substitution is tolerated at C6, C7, and C3. The presence of an electron-withdrawing group at C6 appears to enhance potency in vitro and in vivo. For such benzazepinones, activity is primarily dependent upon lipophilicity, as measured by log P. We believe these compounds must partition into the cell membrane in order to access their receptor. The quaternary methiodide 15k was used to demonstrate that the binding site for benzazepinones is on the intracellular face of the membrane. This work represents the first comprehensive SAR of diltiazem-like calcium channel blockers.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>1311765</pmid><doi>10.1021/jm00082a020</doi><tpages>14</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 1992-02, Vol.35 (4), p.780-793 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_72835963 |
| source | MEDLINE; American Chemical Society Journals |
| subjects | Benzazepines - chemistry Benzazepines - metabolism Binding Sites Calcium Channel Blockers - chemistry Calcium Channel Blockers - metabolism Calcium Channels - metabolism Cell Membrane - metabolism Chemical Phenomena Chemistry, Physical Diltiazem - analogs & derivatives Molecular Structure Structure-Activity Relationship |
| title | Benzazepinone calcium channel blockers. 4. Structure-activity overview and intracellular binding site |
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