Development of Dual-Acting Agents for Thromboxane Receptor Antagonism and Thromboxane Synthase Inhibition. 3. Synthesis and Biological Activities of Oxazolecarboxamide-Substituted ω-Phenyl-ω-(3-pyridyl)alkenoic Acid Derivatives and Related Compounds
A novel series of oxazolecarboxamide-substituted ω-phenyl-ω-(3-pyridyl)alkenoic acid derivatives was discovered as potent dual-acting agents to block the TXA2 receptor and to inhibit the thromboxane synthase (TRA/TSI). Synthesis, structure−activity relationship (SAR), and in vitro and in vivo pharma...
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| Veröffentlicht in: | Journal of medicinal chemistry 1998-12, Vol.41 (27), p.5362-5374 |
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| container_title | Journal of medicinal chemistry |
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| creator | Takeuchi, Kumiko Kohn, Todd J True, Timothy A Mais, Dale E Wikel, James H Utterback, Barbara G Wyss, Virginia L Jakubowski, Joseph A |
| description | A novel series of oxazolecarboxamide-substituted ω-phenyl-ω-(3-pyridyl)alkenoic acid derivatives was discovered as potent dual-acting agents to block the TXA2 receptor and to inhibit the thromboxane synthase (TRA/TSI). Synthesis, structure−activity relationship (SAR), and in vitro and in vivo pharmacology of this series of compounds are described. Modification of the series revolved around the oxazole moiety to increase the hydrophilicity of the compounds and to correlate the biological activity with lipophilicity of the compounds. The most potent in the series was (E)-7-[4-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]phenyl]-7-(3-pyridyl)hept-6-enoic acid (14) with K d = 9.9 ± 0.4 nM for the thromboxane receptor antagonism and IC50 = 55.0 ± 17.9 nM for thromboxane synthase inhibition. The compound 14 was a selective TRA/TSI which exhibited desirable characteristics for oral activity, “shunt” effect to elevate PGI2 level, and absence of agonist activity. |
| doi_str_mv | 10.1021/jm980173n |
| format | Article |
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Synthesis and Biological Activities of Oxazolecarboxamide-Substituted ω-Phenyl-ω-(3-pyridyl)alkenoic Acid Derivatives and Related Compounds</title><source>MEDLINE</source><source>ACS Publications</source><creator>Takeuchi, Kumiko ; Kohn, Todd J ; True, Timothy A ; Mais, Dale E ; Wikel, James H ; Utterback, Barbara G ; Wyss, Virginia L ; Jakubowski, Joseph A</creator><creatorcontrib>Takeuchi, Kumiko ; Kohn, Todd J ; True, Timothy A ; Mais, Dale E ; Wikel, James H ; Utterback, Barbara G ; Wyss, Virginia L ; Jakubowski, Joseph A</creatorcontrib><description>A novel series of oxazolecarboxamide-substituted ω-phenyl-ω-(3-pyridyl)alkenoic acid derivatives was discovered as potent dual-acting agents to block the TXA2 receptor and to inhibit the thromboxane synthase (TRA/TSI). Synthesis, structure−activity relationship (SAR), and in vitro and in vivo pharmacology of this series of compounds are described. Modification of the series revolved around the oxazole moiety to increase the hydrophilicity of the compounds and to correlate the biological activity with lipophilicity of the compounds. The most potent in the series was (E)-7-[4-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]phenyl]-7-(3-pyridyl)hept-6-enoic acid (14) with K d = 9.9 ± 0.4 nM for the thromboxane receptor antagonism and IC50 = 55.0 ± 17.9 nM for thromboxane synthase inhibition. The compound 14 was a selective TRA/TSI which exhibited desirable characteristics for oral activity, “shunt” effect to elevate PGI2 level, and absence of agonist activity.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm980173n</identifier><identifier>PMID: 9876106</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Biological and medical sciences ; Blood Platelets - metabolism ; Blood. Blood coagulation. Reticuloendothelial system ; Drug Design ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Epoprostenol - biosynthesis ; Heptanoic Acids - chemical synthesis ; Heptanoic Acids - chemistry ; Heptanoic Acids - pharmacology ; Humans ; In Vitro Techniques ; Medical sciences ; Oxazoles - chemical synthesis ; Oxazoles - chemistry ; Oxazoles - pharmacology ; Pharmacology. Drug treatments ; Platelet Aggregation - drug effects ; Rats ; Rats, Sprague-Dawley ; Receptors, Thromboxane - antagonists & inhibitors ; Receptors, Thromboxane - metabolism ; Structure-Activity Relationship ; Thromboxane B2 - biosynthesis ; Thromboxane B2 - blood ; Thromboxane-A Synthase - antagonists & inhibitors</subject><ispartof>Journal of medicinal chemistry, 1998-12, Vol.41 (27), p.5362-5374</ispartof><rights>Copyright © 1998 American Chemical Society</rights><rights>1999 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a377t-3da5ff3ac4367971bf681ca1a7d054d26c463ab15ce314fbe98731d999bb04f73</citedby><cites>FETCH-LOGICAL-a377t-3da5ff3ac4367971bf681ca1a7d054d26c463ab15ce314fbe98731d999bb04f73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm980173n$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm980173n$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>315,782,786,2767,27083,27931,27932,56745,56795</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1658203$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9876106$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Takeuchi, Kumiko</creatorcontrib><creatorcontrib>Kohn, Todd J</creatorcontrib><creatorcontrib>True, Timothy A</creatorcontrib><creatorcontrib>Mais, Dale E</creatorcontrib><creatorcontrib>Wikel, James H</creatorcontrib><creatorcontrib>Utterback, Barbara G</creatorcontrib><creatorcontrib>Wyss, Virginia L</creatorcontrib><creatorcontrib>Jakubowski, Joseph A</creatorcontrib><title>Development of Dual-Acting Agents for Thromboxane Receptor Antagonism and Thromboxane Synthase Inhibition. 3. Synthesis and Biological Activities of Oxazolecarboxamide-Substituted ω-Phenyl-ω-(3-pyridyl)alkenoic Acid Derivatives and Related Compounds</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A novel series of oxazolecarboxamide-substituted ω-phenyl-ω-(3-pyridyl)alkenoic acid derivatives was discovered as potent dual-acting agents to block the TXA2 receptor and to inhibit the thromboxane synthase (TRA/TSI). Synthesis, structure−activity relationship (SAR), and in vitro and in vivo pharmacology of this series of compounds are described. Modification of the series revolved around the oxazole moiety to increase the hydrophilicity of the compounds and to correlate the biological activity with lipophilicity of the compounds. The most potent in the series was (E)-7-[4-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]phenyl]-7-(3-pyridyl)hept-6-enoic acid (14) with K d = 9.9 ± 0.4 nM for the thromboxane receptor antagonism and IC50 = 55.0 ± 17.9 nM for thromboxane synthase inhibition. The compound 14 was a selective TRA/TSI which exhibited desirable characteristics for oral activity, “shunt” effect to elevate PGI2 level, and absence of agonist activity.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Blood Platelets - metabolism</subject><subject>Blood. Blood coagulation. Reticuloendothelial system</subject><subject>Drug Design</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Epoprostenol - biosynthesis</subject><subject>Heptanoic Acids - chemical synthesis</subject><subject>Heptanoic Acids - chemistry</subject><subject>Heptanoic Acids - pharmacology</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Medical sciences</subject><subject>Oxazoles - chemical synthesis</subject><subject>Oxazoles - chemistry</subject><subject>Oxazoles - pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Platelet Aggregation - drug effects</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, Thromboxane - antagonists & inhibitors</subject><subject>Receptors, Thromboxane - metabolism</subject><subject>Structure-Activity Relationship</subject><subject>Thromboxane B2 - biosynthesis</subject><subject>Thromboxane B2 - blood</subject><subject>Thromboxane-A Synthase - antagonists & inhibitors</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1998</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkc-O0zAQxiMEWsrCgQdA8oFF7CHFjvOnOZaWXVastGVbLlwix5m07jp2sJ2q4Q14Oh6ICy6pipA42ZrvN9-MvgmClwSPCY7Iu22TTzDJqHoUjEgS4TCe4PhxMMI4isIojejT4Jm1W4wxJRE9C87ySZYSnI6CX3PYgdRtA8ohXaN5x2Q45U6oNZqufdGiWhu02hjdlHrPFKB74NA6X5wqx9ZaCdsgpqp_mGWv3IZZQDdqI0rhhFZjRMdDHaywfzreCy31WnAm0WHkznNgD1vc7dl3LYEzc_BrRAXhsiutE65zUKGfP8LFBlQvQ_97S8O2N6Lq5SWTD6C04N5NVGgORuyYt4Vh2j1Iduie6abVnars8-BJzaSFF8f3PPhy9WE1-xje3l3fzKa3IaNZ5kJasaSuKeMxTbM8I2WdTghnhGUVTuIqSnmcUlaShAMlcV2CD5eSKs_zssRxndHz4M3g2xr9rQPrikZYDlL6pHRnizQnJMN54sHLAeRGW2ugLlojGmb6guDicOjidGjPvjqadmUD1Yk8Xtbrr486sz7g2jDFhf1rmCaTCFOPhQMmrIP9SWbmoUgzmiXFarEsPuWLr_HV7HNx7fmLgWfcFlvdGeWT-896vwF-VNKy</recordid><startdate>19981231</startdate><enddate>19981231</enddate><creator>Takeuchi, Kumiko</creator><creator>Kohn, Todd J</creator><creator>True, Timothy A</creator><creator>Mais, Dale E</creator><creator>Wikel, James H</creator><creator>Utterback, Barbara G</creator><creator>Wyss, Virginia L</creator><creator>Jakubowski, Joseph A</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>19981231</creationdate><title>Development of Dual-Acting Agents for Thromboxane Receptor Antagonism and Thromboxane Synthase Inhibition. 3. Synthesis and Biological Activities of Oxazolecarboxamide-Substituted ω-Phenyl-ω-(3-pyridyl)alkenoic Acid Derivatives and Related Compounds</title><author>Takeuchi, Kumiko ; Kohn, Todd J ; True, Timothy A ; Mais, Dale E ; Wikel, James H ; Utterback, Barbara G ; Wyss, Virginia L ; Jakubowski, Joseph A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a377t-3da5ff3ac4367971bf681ca1a7d054d26c463ab15ce314fbe98731d999bb04f73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1998</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Blood Platelets - metabolism</topic><topic>Blood. Blood coagulation. Reticuloendothelial system</topic><topic>Drug Design</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Epoprostenol - biosynthesis</topic><topic>Heptanoic Acids - chemical synthesis</topic><topic>Heptanoic Acids - chemistry</topic><topic>Heptanoic Acids - pharmacology</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Medical sciences</topic><topic>Oxazoles - chemical synthesis</topic><topic>Oxazoles - chemistry</topic><topic>Oxazoles - pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Platelet Aggregation - drug effects</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptors, Thromboxane - antagonists & inhibitors</topic><topic>Receptors, Thromboxane - metabolism</topic><topic>Structure-Activity Relationship</topic><topic>Thromboxane B2 - biosynthesis</topic><topic>Thromboxane B2 - blood</topic><topic>Thromboxane-A Synthase - antagonists & inhibitors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Takeuchi, Kumiko</creatorcontrib><creatorcontrib>Kohn, Todd J</creatorcontrib><creatorcontrib>True, Timothy A</creatorcontrib><creatorcontrib>Mais, Dale E</creatorcontrib><creatorcontrib>Wikel, James H</creatorcontrib><creatorcontrib>Utterback, Barbara G</creatorcontrib><creatorcontrib>Wyss, Virginia L</creatorcontrib><creatorcontrib>Jakubowski, Joseph A</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>Takeuchi, Kumiko</au><au>Kohn, Todd J</au><au>True, Timothy A</au><au>Mais, Dale E</au><au>Wikel, James H</au><au>Utterback, Barbara G</au><au>Wyss, Virginia L</au><au>Jakubowski, Joseph A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Development of Dual-Acting Agents for Thromboxane Receptor Antagonism and Thromboxane Synthase Inhibition. 3. Synthesis and Biological Activities of Oxazolecarboxamide-Substituted ω-Phenyl-ω-(3-pyridyl)alkenoic Acid Derivatives and Related Compounds</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1998-12-31</date><risdate>1998</risdate><volume>41</volume><issue>27</issue><spage>5362</spage><epage>5374</epage><pages>5362-5374</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>A novel series of oxazolecarboxamide-substituted ω-phenyl-ω-(3-pyridyl)alkenoic acid derivatives was discovered as potent dual-acting agents to block the TXA2 receptor and to inhibit the thromboxane synthase (TRA/TSI). Synthesis, structure−activity relationship (SAR), and in vitro and in vivo pharmacology of this series of compounds are described. Modification of the series revolved around the oxazole moiety to increase the hydrophilicity of the compounds and to correlate the biological activity with lipophilicity of the compounds. The most potent in the series was (E)-7-[4-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]phenyl]-7-(3-pyridyl)hept-6-enoic acid (14) with K d = 9.9 ± 0.4 nM for the thromboxane receptor antagonism and IC50 = 55.0 ± 17.9 nM for thromboxane synthase inhibition. The compound 14 was a selective TRA/TSI which exhibited desirable characteristics for oral activity, “shunt” effect to elevate PGI2 level, and absence of agonist activity.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>9876106</pmid><doi>10.1021/jm980173n</doi><tpages>13</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 1998-12, Vol.41 (27), p.5362-5374 |
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| source | MEDLINE; ACS Publications |
| subjects | Animals Biological and medical sciences Blood Platelets - metabolism Blood. Blood coagulation. Reticuloendothelial system Drug Design Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Epoprostenol - biosynthesis Heptanoic Acids - chemical synthesis Heptanoic Acids - chemistry Heptanoic Acids - pharmacology Humans In Vitro Techniques Medical sciences Oxazoles - chemical synthesis Oxazoles - chemistry Oxazoles - pharmacology Pharmacology. Drug treatments Platelet Aggregation - drug effects Rats Rats, Sprague-Dawley Receptors, Thromboxane - antagonists & inhibitors Receptors, Thromboxane - metabolism Structure-Activity Relationship Thromboxane B2 - biosynthesis Thromboxane B2 - blood Thromboxane-A Synthase - antagonists & inhibitors |
| title | Development of Dual-Acting Agents for Thromboxane Receptor Antagonism and Thromboxane Synthase Inhibition. 3. Synthesis and Biological Activities of Oxazolecarboxamide-Substituted ω-Phenyl-ω-(3-pyridyl)alkenoic Acid Derivatives and Related Compounds |
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