Design, Synthesis, and Activity of a Novel Series of Factor Xa Inhibitors: Optimization of Arylamidine Groups
A novel series of diaryloxypyridines have been designed as selective nanomolar factor Xa (fXa) inhibitors for use as anticoagulants. In this paper, we describe our efforts to identify an additional interaction and a replacement for the distal amidine group that binds in the S3/S4 pocket of fXa. Intr...
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| Veröffentlicht in: | Journal of medicinal chemistry 2002-06, Vol.45 (12), p.2484-2493 |
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| container_title | Journal of medicinal chemistry |
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| creator | Phillips, Gary Guilford, William J Buckman, Brad O Davey, David D Eagen, Keith A Koovakkat, Sunil Liang, Amy McCarrick, Meg Mohan, Raju Ng, Howard P Pinkerton, Michael Subramanyam, Babu Ho, Elena Trinh, Lan Whitlow, Marc Wu, Shung Xu, Wei Morrissey, Michael M |
| description | A novel series of diaryloxypyridines have been designed as selective nanomolar factor Xa (fXa) inhibitors for use as anticoagulants. In this paper, we describe our efforts to identify an additional interaction and a replacement for the distal amidine group that binds in the S3/S4 pocket of fXa. Introduction of a hydroxyl group para to the proximal amidine group increases the potency vs fXa by 1−2 orders of magnitude, which is the result of a hydrogen bond to Ser195 of the catalytic triad. A methyl imidazoline and a dimethylamide are good alternatives for the second amidine. These substitutions have increased the selectivity vs the related serine proteases trypsin and thrombin. The synthesis, in vitro activity, and hypothetical modes of binding to fXa based on trypsin crystallographic data are outlined. |
| doi_str_mv | 10.1021/jm0200660 |
| format | Article |
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In this paper, we describe our efforts to identify an additional interaction and a replacement for the distal amidine group that binds in the S3/S4 pocket of fXa. Introduction of a hydroxyl group para to the proximal amidine group increases the potency vs fXa by 1−2 orders of magnitude, which is the result of a hydrogen bond to Ser195 of the catalytic triad. A methyl imidazoline and a dimethylamide are good alternatives for the second amidine. These substitutions have increased the selectivity vs the related serine proteases trypsin and thrombin. The synthesis, in vitro activity, and hypothetical modes of binding to fXa based on trypsin crystallographic data are outlined.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm0200660</identifier><identifier>PMID: 12036356</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Amidines - chemical synthesis ; Amidines - chemistry ; Amidines - pharmacokinetics ; Animals ; Biological and medical sciences ; Blood. Blood coagulation. Reticuloendothelial system ; Chromatography, High Pressure Liquid ; Crystallography, X-Ray ; Factor Xa - chemistry ; Factor Xa Inhibitors ; Humans ; Medical sciences ; Models, Molecular ; Pharmacology. Drug treatments ; Rats ; Serine Proteinase Inhibitors - chemical synthesis ; Serine Proteinase Inhibitors - chemistry ; Serine Proteinase Inhibitors - pharmacokinetics ; Structure-Activity Relationship ; Thrombin - chemistry ; Trypsin - chemistry</subject><ispartof>Journal of medicinal chemistry, 2002-06, Vol.45 (12), p.2484-2493</ispartof><rights>Copyright © 2002 American Chemical Society</rights><rights>2002 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a445t-5552b392e257b20d06f210993de85942c28549bb46ed6ade5d71221d5459e483</citedby><cites>FETCH-LOGICAL-a445t-5552b392e257b20d06f210993de85942c28549bb46ed6ade5d71221d5459e483</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/jm0200660$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm0200660$$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=13696256$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12036356$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Phillips, Gary</creatorcontrib><creatorcontrib>Guilford, William J</creatorcontrib><creatorcontrib>Buckman, Brad O</creatorcontrib><creatorcontrib>Davey, David D</creatorcontrib><creatorcontrib>Eagen, Keith A</creatorcontrib><creatorcontrib>Koovakkat, Sunil</creatorcontrib><creatorcontrib>Liang, Amy</creatorcontrib><creatorcontrib>McCarrick, Meg</creatorcontrib><creatorcontrib>Mohan, Raju</creatorcontrib><creatorcontrib>Ng, Howard P</creatorcontrib><creatorcontrib>Pinkerton, Michael</creatorcontrib><creatorcontrib>Subramanyam, Babu</creatorcontrib><creatorcontrib>Ho, Elena</creatorcontrib><creatorcontrib>Trinh, Lan</creatorcontrib><creatorcontrib>Whitlow, Marc</creatorcontrib><creatorcontrib>Wu, Shung</creatorcontrib><creatorcontrib>Xu, Wei</creatorcontrib><creatorcontrib>Morrissey, Michael M</creatorcontrib><title>Design, Synthesis, and Activity of a Novel Series of Factor Xa Inhibitors: Optimization of Arylamidine Groups</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A novel series of diaryloxypyridines have been designed as selective nanomolar factor Xa (fXa) inhibitors for use as anticoagulants. In this paper, we describe our efforts to identify an additional interaction and a replacement for the distal amidine group that binds in the S3/S4 pocket of fXa. Introduction of a hydroxyl group para to the proximal amidine group increases the potency vs fXa by 1−2 orders of magnitude, which is the result of a hydrogen bond to Ser195 of the catalytic triad. A methyl imidazoline and a dimethylamide are good alternatives for the second amidine. These substitutions have increased the selectivity vs the related serine proteases trypsin and thrombin. The synthesis, in vitro activity, and hypothetical modes of binding to fXa based on trypsin crystallographic data are outlined.</description><subject>Amidines - chemical synthesis</subject><subject>Amidines - chemistry</subject><subject>Amidines - pharmacokinetics</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Blood. Blood coagulation. Reticuloendothelial system</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Crystallography, X-Ray</subject><subject>Factor Xa - chemistry</subject><subject>Factor Xa Inhibitors</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>Pharmacology. Drug treatments</subject><subject>Rats</subject><subject>Serine Proteinase Inhibitors - chemical synthesis</subject><subject>Serine Proteinase Inhibitors - chemistry</subject><subject>Serine Proteinase Inhibitors - pharmacokinetics</subject><subject>Structure-Activity Relationship</subject><subject>Thrombin - chemistry</subject><subject>Trypsin - chemistry</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkMtuEzEUhi0EoiGw4AWQNyAhdeD4-DIz3UWFlEJFkZIFYmN5xh7qMDfsmYqwYstr8iRMSNRsWJ3bp19HHyFPGbxigOz1pgEEUArukRmTCInIQNwnMwDEBBXyE_Ioxg0AcIb8ITlhCFxxqWakf-Oi_9qe0tW2HW6mPp5S01q6KAd_64ct7Spq6Mfu1tV05YJ3cbdZmnLoAv1s6GV74ws_DfHsz6_f9LoffON_msF37Q5chG1tGm996-hF6MY-PiYPKlNH9-RQ52S9fLs-f5dcXV9cni-uEiOEHBIpJRY8R4cyLRAsqAoZ5Dm3LpO5wBIzKfKiEMpZZayTNmWIzEohcycyPicv9rF96L6PLg668bF0dW1a141RpyyVDCY1c_JyD5ahizG4SvfBNyZsNQO9s6vv7E7ss0PoWDTOHsmDzgl4fgBMLE1dBdOWPh45rnKF_7hkz_k4uB93dxO-aZXyVOr1p5X-8n4JYpV90Otjrimj3nRjaCd1_3nwL95Xm88</recordid><startdate>20020606</startdate><enddate>20020606</enddate><creator>Phillips, Gary</creator><creator>Guilford, William J</creator><creator>Buckman, Brad O</creator><creator>Davey, David D</creator><creator>Eagen, Keith A</creator><creator>Koovakkat, Sunil</creator><creator>Liang, Amy</creator><creator>McCarrick, Meg</creator><creator>Mohan, Raju</creator><creator>Ng, Howard P</creator><creator>Pinkerton, Michael</creator><creator>Subramanyam, Babu</creator><creator>Ho, Elena</creator><creator>Trinh, Lan</creator><creator>Whitlow, Marc</creator><creator>Wu, Shung</creator><creator>Xu, Wei</creator><creator>Morrissey, Michael M</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>20020606</creationdate><title>Design, Synthesis, and Activity of a Novel Series of Factor Xa Inhibitors: Optimization of Arylamidine Groups</title><author>Phillips, Gary ; Guilford, William J ; Buckman, Brad O ; Davey, David D ; Eagen, Keith A ; Koovakkat, Sunil ; Liang, Amy ; McCarrick, Meg ; Mohan, Raju ; Ng, Howard P ; Pinkerton, Michael ; Subramanyam, Babu ; Ho, Elena ; Trinh, Lan ; Whitlow, Marc ; Wu, Shung ; Xu, Wei ; Morrissey, Michael M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a445t-5552b392e257b20d06f210993de85942c28549bb46ed6ade5d71221d5459e483</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Amidines - chemical synthesis</topic><topic>Amidines - chemistry</topic><topic>Amidines - pharmacokinetics</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Blood. Blood coagulation. Reticuloendothelial system</topic><topic>Chromatography, High Pressure Liquid</topic><topic>Crystallography, X-Ray</topic><topic>Factor Xa - chemistry</topic><topic>Factor Xa Inhibitors</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Models, Molecular</topic><topic>Pharmacology. 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Med. Chem</addtitle><date>2002-06-06</date><risdate>2002</risdate><volume>45</volume><issue>12</issue><spage>2484</spage><epage>2493</epage><pages>2484-2493</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>A novel series of diaryloxypyridines have been designed as selective nanomolar factor Xa (fXa) inhibitors for use as anticoagulants. In this paper, we describe our efforts to identify an additional interaction and a replacement for the distal amidine group that binds in the S3/S4 pocket of fXa. Introduction of a hydroxyl group para to the proximal amidine group increases the potency vs fXa by 1−2 orders of magnitude, which is the result of a hydrogen bond to Ser195 of the catalytic triad. A methyl imidazoline and a dimethylamide are good alternatives for the second amidine. These substitutions have increased the selectivity vs the related serine proteases trypsin and thrombin. The synthesis, in vitro activity, and hypothetical modes of binding to fXa based on trypsin crystallographic data are outlined.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>12036356</pmid><doi>10.1021/jm0200660</doi><tpages>10</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2002-06, Vol.45 (12), p.2484-2493 |
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| subjects | Amidines - chemical synthesis Amidines - chemistry Amidines - pharmacokinetics Animals Biological and medical sciences Blood. Blood coagulation. Reticuloendothelial system Chromatography, High Pressure Liquid Crystallography, X-Ray Factor Xa - chemistry Factor Xa Inhibitors Humans Medical sciences Models, Molecular Pharmacology. Drug treatments Rats Serine Proteinase Inhibitors - chemical synthesis Serine Proteinase Inhibitors - chemistry Serine Proteinase Inhibitors - pharmacokinetics Structure-Activity Relationship Thrombin - chemistry Trypsin - chemistry |
| title | Design, Synthesis, and Activity of a Novel Series of Factor Xa Inhibitors: Optimization of Arylamidine Groups |
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