Structure-activity relationships in an imidazole-based series of thromboxane synthase inhibitors
Analogues of 4-[[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)methoxy]methyl] ethoxy]methyl]benzoic acid (5m) were prepared and evaluated as thromboxane synthase inhibitors. A series of esters of 5m showed a parabolic relationship between lipophilicity and inhibition of TxB2 generation in intact platel...
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| Veröffentlicht in: | Journal of medicinal chemistry 1987-09, Vol.30 (9), p.1588-1595 |
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| container_end_page | 1595 |
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| container_issue | 9 |
| container_start_page | 1588 |
| container_title | Journal of medicinal chemistry |
| container_volume | 30 |
| creator | Manley, Paul W. Allanson, Nigel M. Booth, Robert F. G. Buckle, Philip E. Kuzniar, Edward J. Lad, Nagin Lai, Steve M. F. Lunt, David O. Tuffin, David P. |
| description | Analogues of 4-[[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)methoxy]methyl] ethoxy]methyl]benzoic acid (5m) were prepared and evaluated as thromboxane synthase inhibitors. A series of esters of 5m showed a parabolic relationship between lipophilicity and inhibition of TxB2 generation in intact platelets, with activities up to 50 times greater than that of dazoxiben. However, on administration to rabbits the ethyl ester 5d had a short duration of action, due to rapid metabolism and excretion via deesterification and beta-glucuronidation. Attempts at replacing the carboxylate group with other potential pharmacophores were unsuccessful. |
| doi_str_mv | 10.1021/jm00392a011 |
| format | Article |
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G.</creatorcontrib><creatorcontrib>Buckle, Philip E.</creatorcontrib><creatorcontrib>Kuzniar, Edward J.</creatorcontrib><creatorcontrib>Lad, Nagin</creatorcontrib><creatorcontrib>Lai, Steve M. F.</creatorcontrib><creatorcontrib>Lunt, David O.</creatorcontrib><creatorcontrib>Tuffin, David P.</creatorcontrib><title>Structure-activity relationships in an imidazole-based series of thromboxane synthase inhibitors</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Analogues of 4-[[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)methoxy]methyl] ethoxy]methyl]benzoic acid (5m) were prepared and evaluated as thromboxane synthase inhibitors. A series of esters of 5m showed a parabolic relationship between lipophilicity and inhibition of TxB2 generation in intact platelets, with activities up to 50 times greater than that of dazoxiben. However, on administration to rabbits the ethyl ester 5d had a short duration of action, due to rapid metabolism and excretion via deesterification and beta-glucuronidation. Attempts at replacing the carboxylate group with other potential pharmacophores were unsuccessful.</description><subject>Animals</subject><subject>Blood Platelets - drug effects</subject><subject>Blood Platelets - enzymology</subject><subject>Chemistry</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Collagen - pharmacology</subject><subject>Epoprostenol - biosynthesis</subject><subject>Exact sciences and technology</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>Humans</subject><subject>Imidazoles - pharmacology</subject><subject>Organic chemistry</subject><subject>Preparations and properties</subject><subject>Rabbits</subject><subject>Structure-Activity Relationship</subject><subject>Thromboxane A2 - 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>1987</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0E2LFDEQBuAgyjqunjwLfRD3IK357u6jLO6qLCjsiOIlVtJpJmN3Z0ylZcdfb2SGwYOnOrxPFcVLyFNGXzHK2evtRKnoOFDG7pEVU5zWsqXyPllRynnNNRcPySPELS2OcXFGzoSgqpNqRb7f5rS4vCRfg8vhV8j7KvkRcogzbsIOqzBXMFdhCj38jqOvLaDvK_QpeKziUOVNipONdzD7Cvdz3pS8LG2CDTkmfEweDDCif3Kc5-Tz1dv15bv65uP1-8s3NzWIVuRadtp2rWIto6A9b5SVoqcgGLNWS6-dZqCEkgC-ZUMne9k2VmnFbevASxDn5MXh7i7Fn4vHbKaAzo9j-SsuaJpGN1wqWeDLA3QpIiY_mF0KE6S9YdT87dP802fRz45nFzv5_mSPBZb8-TEHdDAOCWYX8MTa0rcSXWH1gQXM_u4UQ_phdCMaZdafbs21-PZ1zegH86X4i4MHh2YblzSX7v774B_Jn5m7</recordid><startdate>19870901</startdate><enddate>19870901</enddate><creator>Manley, Paul W.</creator><creator>Allanson, Nigel M.</creator><creator>Booth, Robert F. 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F.</au><au>Lunt, David O.</au><au>Tuffin, David P.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure-activity relationships in an imidazole-based series of thromboxane synthase inhibitors</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1987-09-01</date><risdate>1987</risdate><volume>30</volume><issue>9</issue><spage>1588</spage><epage>1595</epage><pages>1588-1595</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Analogues of 4-[[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)methoxy]methyl] ethoxy]methyl]benzoic acid (5m) were prepared and evaluated as thromboxane synthase inhibitors. A series of esters of 5m showed a parabolic relationship between lipophilicity and inhibition of TxB2 generation in intact platelets, with activities up to 50 times greater than that of dazoxiben. 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| ispartof | Journal of medicinal chemistry, 1987-09, Vol.30 (9), p.1588-1595 |
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| subjects | Animals Blood Platelets - drug effects Blood Platelets - enzymology Chemistry Chromatography, High Pressure Liquid Collagen - pharmacology Epoprostenol - biosynthesis Exact sciences and technology Heterocyclic compounds Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings Humans Imidazoles - pharmacology Organic chemistry Preparations and properties Rabbits Structure-Activity Relationship Thromboxane A2 - biosynthesis Thromboxane B2 - blood Thromboxane-A Synthase - antagonists & inhibitors |
| title | Structure-activity relationships in an imidazole-based series of thromboxane synthase inhibitors |
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