Molecular design, synthesis, and antiinflammatory activity of a series of .beta.-aminoxypropionic acids
Previous experimental and theoretical studies carried out on the mechanism of action of adrenergic drugs have shown that the (methyleneaminoxy)methyl moiety (C = NOCH2, MAOMM) can be considered as a "bioisostere" of an aryl group (Ar). On this basis, a series of substituted beta-aminoxypro...
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Veröffentlicht in: | Journal of medicinal chemistry 1990-05, Vol.33 (5), p.1423-1430 |
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creator | Macchia, Bruno Balsamo, A Lapucci, A Macchia, F Martinelli, A Nencetti, S Orlandini, E Baldacci, M Mengozzi, G |
description | Previous experimental and theoretical studies carried out on the mechanism of action of adrenergic drugs have shown that the (methyleneaminoxy)methyl moiety (C = NOCH2, MAOMM) can be considered as a "bioisostere" of an aryl group (Ar). On this basis, a series of substituted beta-aminoxypropionic acids (AOPAs) were synthesized as analogues of antiinflammatory arylacetic acids (ArAAs), in which the Ar portion is substituted by the MAOMM, with the aim of evaluating whether any antiinflammatory activity could be obtained from this class of drugs after the substitution of the Ar with the MAOMM. The antiinflammatory activity of the AOPAs synthesized was determined by carageenan-induced rat paw edema, using diclofenac as the reference drug. The pharmacological data showed that most of the AOPAs examined exhibit a significant antiinflammatory activity, which in the case of the (E)-3-(benzylideneaminoxy)propionic acid (7q) is very close to that of the reference drug. Structural and theoretical studies were carried out in order to compare the conformation and the molecular reactivity of the AOPAs with those of the ArAAs. Pharmacological results showed that the ArAAs also generally exhibit an antiinflammatory activity after the substitution of the Ar with the MAOMM, thus supporting the hypothesis of a bioisosterelike relationship between these two moieties in this class of NSAIDs. |
doi_str_mv | 10.1021/jm00167a023 |
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On this basis, a series of substituted beta-aminoxypropionic acids (AOPAs) were synthesized as analogues of antiinflammatory arylacetic acids (ArAAs), in which the Ar portion is substituted by the MAOMM, with the aim of evaluating whether any antiinflammatory activity could be obtained from this class of drugs after the substitution of the Ar with the MAOMM. The antiinflammatory activity of the AOPAs synthesized was determined by carageenan-induced rat paw edema, using diclofenac as the reference drug. The pharmacological data showed that most of the AOPAs examined exhibit a significant antiinflammatory activity, which in the case of the (E)-3-(benzylideneaminoxy)propionic acid (7q) is very close to that of the reference drug. Structural and theoretical studies were carried out in order to compare the conformation and the molecular reactivity of the AOPAs with those of the ArAAs. Pharmacological results showed that the ArAAs also generally exhibit an antiinflammatory activity after the substitution of the Ar with the MAOMM, thus supporting the hypothesis of a bioisosterelike relationship between these two moieties in this class of NSAIDs.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00167a023</identifier><identifier>PMID: 2329564</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Alanine - analogs & derivatives ; Alanine - chemical synthesis ; Animals ; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis ; Biological and medical sciences ; Bones, joints and connective tissue. Antiinflammatory agents ; Chemical Phenomena ; Chemistry ; Drug Design ; Female ; Medical sciences ; Models, Molecular ; Pharmacology. Drug treatments ; Rats ; Rats, Inbred Strains ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 1990-05, Vol.33 (5), p.1423-1430</ispartof><rights>1991 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a384t-b976e225f3149d621b57a2c720adc1ae1883d714f467029f6589f71efbda406c3</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/jm00167a023$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00167a023$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=19458356$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/2329564$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Macchia, Bruno</creatorcontrib><creatorcontrib>Balsamo, A</creatorcontrib><creatorcontrib>Lapucci, A</creatorcontrib><creatorcontrib>Macchia, F</creatorcontrib><creatorcontrib>Martinelli, A</creatorcontrib><creatorcontrib>Nencetti, S</creatorcontrib><creatorcontrib>Orlandini, E</creatorcontrib><creatorcontrib>Baldacci, M</creatorcontrib><creatorcontrib>Mengozzi, G</creatorcontrib><title>Molecular design, synthesis, and antiinflammatory activity of a series of .beta.-aminoxypropionic acids</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Previous experimental and theoretical studies carried out on the mechanism of action of adrenergic drugs have shown that the (methyleneaminoxy)methyl moiety (C = NOCH2, MAOMM) can be considered as a "bioisostere" of an aryl group (Ar). On this basis, a series of substituted beta-aminoxypropionic acids (AOPAs) were synthesized as analogues of antiinflammatory arylacetic acids (ArAAs), in which the Ar portion is substituted by the MAOMM, with the aim of evaluating whether any antiinflammatory activity could be obtained from this class of drugs after the substitution of the Ar with the MAOMM. The antiinflammatory activity of the AOPAs synthesized was determined by carageenan-induced rat paw edema, using diclofenac as the reference drug. The pharmacological data showed that most of the AOPAs examined exhibit a significant antiinflammatory activity, which in the case of the (E)-3-(benzylideneaminoxy)propionic acid (7q) is very close to that of the reference drug. Structural and theoretical studies were carried out in order to compare the conformation and the molecular reactivity of the AOPAs with those of the ArAAs. Pharmacological results showed that the ArAAs also generally exhibit an antiinflammatory activity after the substitution of the Ar with the MAOMM, thus supporting the hypothesis of a bioisosterelike relationship between these two moieties in this class of NSAIDs.</description><subject>Alanine - analogs & derivatives</subject><subject>Alanine - chemical synthesis</subject><subject>Animals</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis</subject><subject>Biological and medical sciences</subject><subject>Bones, joints and connective tissue. Antiinflammatory agents</subject><subject>Chemical Phenomena</subject><subject>Chemistry</subject><subject>Drug Design</subject><subject>Female</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>Pharmacology. Drug treatments</subject><subject>Rats</subject><subject>Rats, Inbred Strains</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>eNpt0M1rFDEYBvAgSt1WT56FuagHO2u-M3OsS6tii4IVwUt4J5PUrDOTNclI5783ZZfqwUPIC8-PN-FB6BnBa4IpebMdMSZSAabsAVoRQXHNG8wfohXGlNZUUvYYHae0xRgzQtkROqKMtkLyFbq5CoM18wCx6m3yN9NplZYp_yhzOq1g6svJ3k9ugHGEHOJSgcn-t89LFVwFVbLR23Q3rzubYV3D6Kdwu-xi2PkweVO879MT9MjBkOzTw32Cvl6cX2_e15ef3n3YnF3WwBqe665V0lIqHCO87SUlnVBAjaIYekPAkqZhvSLccakwbZ0UTesUsa7rgWNp2Al6ud9b3v8125T16JOxwwCTDXPSqlXFYVHg6z00MaQUrdO76EeIiyZY39Wq_6m16OeHtXM32v7eHnos-YtDDsnA4CJMxqe_K1suGiZkcfXe-ZTt7X0O8aeWiimhrz9_0XJz8U1cvf2uPxb_au_BJL0Nc5xKef_94R-ZT5t3</recordid><startdate>19900501</startdate><enddate>19900501</enddate><creator>Macchia, Bruno</creator><creator>Balsamo, A</creator><creator>Lapucci, A</creator><creator>Macchia, F</creator><creator>Martinelli, A</creator><creator>Nencetti, S</creator><creator>Orlandini, E</creator><creator>Baldacci, M</creator><creator>Mengozzi, G</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>19900501</creationdate><title>Molecular design, synthesis, and antiinflammatory activity of a series of .beta.-aminoxypropionic acids</title><author>Macchia, Bruno ; Balsamo, A ; Lapucci, A ; Macchia, F ; Martinelli, A ; Nencetti, S ; Orlandini, E ; Baldacci, M ; Mengozzi, G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a384t-b976e225f3149d621b57a2c720adc1ae1883d714f467029f6589f71efbda406c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1990</creationdate><topic>Alanine - analogs & derivatives</topic><topic>Alanine - chemical synthesis</topic><topic>Animals</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis</topic><topic>Biological and medical sciences</topic><topic>Bones, joints and connective tissue. Antiinflammatory agents</topic><topic>Chemical Phenomena</topic><topic>Chemistry</topic><topic>Drug Design</topic><topic>Female</topic><topic>Medical sciences</topic><topic>Models, Molecular</topic><topic>Pharmacology. Drug treatments</topic><topic>Rats</topic><topic>Rats, Inbred Strains</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Macchia, Bruno</creatorcontrib><creatorcontrib>Balsamo, A</creatorcontrib><creatorcontrib>Lapucci, A</creatorcontrib><creatorcontrib>Macchia, F</creatorcontrib><creatorcontrib>Martinelli, A</creatorcontrib><creatorcontrib>Nencetti, S</creatorcontrib><creatorcontrib>Orlandini, E</creatorcontrib><creatorcontrib>Baldacci, M</creatorcontrib><creatorcontrib>Mengozzi, G</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>Macchia, Bruno</au><au>Balsamo, A</au><au>Lapucci, A</au><au>Macchia, F</au><au>Martinelli, A</au><au>Nencetti, S</au><au>Orlandini, E</au><au>Baldacci, M</au><au>Mengozzi, G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Molecular design, synthesis, and antiinflammatory activity of a series of .beta.-aminoxypropionic acids</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1990-05-01</date><risdate>1990</risdate><volume>33</volume><issue>5</issue><spage>1423</spage><epage>1430</epage><pages>1423-1430</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Previous experimental and theoretical studies carried out on the mechanism of action of adrenergic drugs have shown that the (methyleneaminoxy)methyl moiety (C = NOCH2, MAOMM) can be considered as a "bioisostere" of an aryl group (Ar). On this basis, a series of substituted beta-aminoxypropionic acids (AOPAs) were synthesized as analogues of antiinflammatory arylacetic acids (ArAAs), in which the Ar portion is substituted by the MAOMM, with the aim of evaluating whether any antiinflammatory activity could be obtained from this class of drugs after the substitution of the Ar with the MAOMM. The antiinflammatory activity of the AOPAs synthesized was determined by carageenan-induced rat paw edema, using diclofenac as the reference drug. The pharmacological data showed that most of the AOPAs examined exhibit a significant antiinflammatory activity, which in the case of the (E)-3-(benzylideneaminoxy)propionic acid (7q) is very close to that of the reference drug. Structural and theoretical studies were carried out in order to compare the conformation and the molecular reactivity of the AOPAs with those of the ArAAs. Pharmacological results showed that the ArAAs also generally exhibit an antiinflammatory activity after the substitution of the Ar with the MAOMM, thus supporting the hypothesis of a bioisosterelike relationship between these two moieties in this class of NSAIDs.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>2329564</pmid><doi>10.1021/jm00167a023</doi><tpages>8</tpages></addata></record> |
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subjects | Alanine - analogs & derivatives Alanine - chemical synthesis Animals Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Chemical Phenomena Chemistry Drug Design Female Medical sciences Models, Molecular Pharmacology. Drug treatments Rats Rats, Inbred Strains Structure-Activity Relationship |
title | Molecular design, synthesis, and antiinflammatory activity of a series of .beta.-aminoxypropionic acids |
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