Synthesis and quantitative structure-activity relationships of diclofenac analogs
The synthesis of a series of 2-anilinophenylacetic acids, close analogues of diclofenac, is described. These compounds were tested in two models used for evaluating the activity of nonsteroidal antiinflammatory drugs (NSAID's), inhibition of cyclooxygenase enzyme activity in vitro, and adjuvant...
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| Veröffentlicht in: | Journal of medicinal chemistry 1990-09, Vol.33 (9), p.2358-2368 |
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| container_end_page | 2368 |
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| container_title | Journal of medicinal chemistry |
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| creator | Moser, Peter Sallmann, Alfred Wiesenberg, Irmgard |
| description | The synthesis of a series of 2-anilinophenylacetic acids, close analogues of diclofenac, is described. These compounds were tested in two models used for evaluating the activity of nonsteroidal antiinflammatory drugs (NSAID's), inhibition of cyclooxygenase enzyme activity in vitro, and adjuvant-induced arthritis (AdA) in rats. Statistically significant correlations were found between the inhibitory activities of the compounds in these two models, indicating that cyclooxygenase inhibition seems to be the underlying mechanism for the antiinflammatory activity of these compounds. Quantitative structure-activity relationship (QSAR) analysis revealed that the crucial parameters for activity in both models were the lipophilicity and the angle of twist between the two phenyl rings. Optimal activities were associated with halogen or alkyl substituents in both ortho positions of the anilino ring. Compounds with OH groups in addition to two ortho substituents or compounds with only one or no ortho substituents were less active. |
| doi_str_mv | 10.1021/jm00171a008 |
| format | Article |
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These compounds were tested in two models used for evaluating the activity of nonsteroidal antiinflammatory drugs (NSAID's), inhibition of cyclooxygenase enzyme activity in vitro, and adjuvant-induced arthritis (AdA) in rats. Statistically significant correlations were found between the inhibitory activities of the compounds in these two models, indicating that cyclooxygenase inhibition seems to be the underlying mechanism for the antiinflammatory activity of these compounds. Quantitative structure-activity relationship (QSAR) analysis revealed that the crucial parameters for activity in both models were the lipophilicity and the angle of twist between the two phenyl rings. Optimal activities were associated with halogen or alkyl substituents in both ortho positions of the anilino ring. Compounds with OH groups in addition to two ortho substituents or compounds with only one or no ortho substituents were less active.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00171a008</identifier><identifier>PMID: 2118185</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis ; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use ; Arthritis, Experimental - drug therapy ; Chemical Phenomena ; Chemistry ; Cyclooxygenase Inhibitors ; Diclofenac - analogs & derivatives ; Exact sciences and technology ; Male ; Noncondensed benzenic compounds ; Organic chemistry ; Preparations and properties ; Rats ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 1990-09, Vol.33 (9), p.2358-2368</ispartof><rights>1992 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a449t-c6971b06c0cdfe95bb3f33df27cc87471af817bede291b3aec913050f5806ca63</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/jm00171a008$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00171a008$$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=5233022$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/2118185$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Moser, Peter</creatorcontrib><creatorcontrib>Sallmann, Alfred</creatorcontrib><creatorcontrib>Wiesenberg, Irmgard</creatorcontrib><title>Synthesis and quantitative structure-activity relationships of diclofenac analogs</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The synthesis of a series of 2-anilinophenylacetic acids, close analogues of diclofenac, is described. These compounds were tested in two models used for evaluating the activity of nonsteroidal antiinflammatory drugs (NSAID's), inhibition of cyclooxygenase enzyme activity in vitro, and adjuvant-induced arthritis (AdA) in rats. Statistically significant correlations were found between the inhibitory activities of the compounds in these two models, indicating that cyclooxygenase inhibition seems to be the underlying mechanism for the antiinflammatory activity of these compounds. Quantitative structure-activity relationship (QSAR) analysis revealed that the crucial parameters for activity in both models were the lipophilicity and the angle of twist between the two phenyl rings. Optimal activities were associated with halogen or alkyl substituents in both ortho positions of the anilino ring. Compounds with OH groups in addition to two ortho substituents or compounds with only one or no ortho substituents were less active.</description><subject>Animals</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - therapeutic use</subject><subject>Arthritis, Experimental - drug therapy</subject><subject>Chemical Phenomena</subject><subject>Chemistry</subject><subject>Cyclooxygenase Inhibitors</subject><subject>Diclofenac - analogs & derivatives</subject><subject>Exact sciences and technology</subject><subject>Male</subject><subject>Noncondensed benzenic compounds</subject><subject>Organic chemistry</subject><subject>Preparations and properties</subject><subject>Rats</subject><subject>Structure-Activity Relationship</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>eNptkEFv1DAQRi1EVbaFE2ekHBA9oMDYTmLniFa0RapUYIs4WhPHpl6yydbjVOy_x2hXqx44jTTfm9HMY-w1hw8cBP-43gBwxRFAP2MLXgsoKw3Vc7YAEKIUjZAv2BnRGgAkF_KUnQrONdf1gn1b7cZ07yhQgWNfPMw4ppAwhUdXUIqzTXN0JdrcCGlXRDfkbBrpPmypmHzRBztM3o1o8zwO0y96yU48DuReHeo5-3H5-W55Xd7cXn1ZfropsaraVNqmVbyDxoLtvWvrrpNeyt4LZa1WVX7Ha6461zvR8k6isy2XUIOvdR7CRp6zd_u92zg9zI6S2QSybhhwdNNMRrVto2vFM_h-D9o4EUXnzTaGDcad4WD-CTRPBGb6zWHt3G1cf2QPxnL-9pAjWRx8xNEGOmK1kDJLz1i5xwIl9-cYY_xtGiVVbe6-rsz3pb76qVeX5jrzF3seLZn1NMcsk_574F-aVJUc</recordid><startdate>19900901</startdate><enddate>19900901</enddate><creator>Moser, Peter</creator><creator>Sallmann, Alfred</creator><creator>Wiesenberg, Irmgard</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>19900901</creationdate><title>Synthesis and quantitative structure-activity relationships of diclofenac analogs</title><author>Moser, Peter ; Sallmann, Alfred ; Wiesenberg, Irmgard</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a449t-c6971b06c0cdfe95bb3f33df27cc87471af817bede291b3aec913050f5806ca63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1990</creationdate><topic>Animals</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - therapeutic use</topic><topic>Arthritis, Experimental - drug therapy</topic><topic>Chemical Phenomena</topic><topic>Chemistry</topic><topic>Cyclooxygenase Inhibitors</topic><topic>Diclofenac - analogs & derivatives</topic><topic>Exact sciences and technology</topic><topic>Male</topic><topic>Noncondensed benzenic compounds</topic><topic>Organic chemistry</topic><topic>Preparations and properties</topic><topic>Rats</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Moser, Peter</creatorcontrib><creatorcontrib>Sallmann, Alfred</creatorcontrib><creatorcontrib>Wiesenberg, Irmgard</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>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Moser, Peter</au><au>Sallmann, Alfred</au><au>Wiesenberg, Irmgard</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and quantitative structure-activity relationships of diclofenac analogs</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1990-09-01</date><risdate>1990</risdate><volume>33</volume><issue>9</issue><spage>2358</spage><epage>2368</epage><pages>2358-2368</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>The synthesis of a series of 2-anilinophenylacetic acids, close analogues of diclofenac, is described. These compounds were tested in two models used for evaluating the activity of nonsteroidal antiinflammatory drugs (NSAID's), inhibition of cyclooxygenase enzyme activity in vitro, and adjuvant-induced arthritis (AdA) in rats. Statistically significant correlations were found between the inhibitory activities of the compounds in these two models, indicating that cyclooxygenase inhibition seems to be the underlying mechanism for the antiinflammatory activity of these compounds. Quantitative structure-activity relationship (QSAR) analysis revealed that the crucial parameters for activity in both models were the lipophilicity and the angle of twist between the two phenyl rings. Optimal activities were associated with halogen or alkyl substituents in both ortho positions of the anilino ring. Compounds with OH groups in addition to two ortho substituents or compounds with only one or no ortho substituents were less active.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>2118185</pmid><doi>10.1021/jm00171a008</doi><tpages>11</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 1990-09, Vol.33 (9), p.2358-2368 |
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| language | eng |
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| source | ACS Publications; MEDLINE |
| subjects | Animals Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis Anti-Inflammatory Agents, Non-Steroidal - therapeutic use Arthritis, Experimental - drug therapy Chemical Phenomena Chemistry Cyclooxygenase Inhibitors Diclofenac - analogs & derivatives Exact sciences and technology Male Noncondensed benzenic compounds Organic chemistry Preparations and properties Rats Structure-Activity Relationship |
| title | Synthesis and quantitative structure-activity relationships of diclofenac analogs |
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