Stereoselective synthesis and biological evaluation of 3,4-diaminocyclohexanecarboxylic acid derivatives as factor Xa inhibitors
There have been few reports on synthetic methods for cis-1,2-diaminocyclohexane bearing a third ring substituent. Starting from 3-cyclohexenecarboxylic acid, we developed efficient methods for synthesizing the 3,4-diaminocyclohexanecarboxylic acid derivatives 2– 5. We also evaluated their anti-Xa an...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2008-08, Vol.18 (16), p.4587-4592 |
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| container_title | Bioorganic & medicinal chemistry |
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| creator | Nagata, Tsutomu Nagamochi, Masatoshi Kobayashi, Shozo Komoriya, Satoshi Yoshino, Toshiharu Kanno, Hideyuki |
| description | There have been few reports on synthetic methods for
cis-1,2-diaminocyclohexane bearing a third ring substituent. Starting from 3-cyclohexenecarboxylic acid, we developed efficient methods for synthesizing the 3,4-diaminocyclohexanecarboxylic acid derivatives
2–
5. We also evaluated their anti-Xa and anticoagulant activities. Among the compounds, acid
2a and amide
2b exhibited the most potent in vitro anti-fXa activity, indicating that the position and stereochemistry of a polar functional group on the cyclohexane ring greatly affected the in vitro anti-fXa activity. |
| doi_str_mv | 10.1016/j.bmcl.2008.07.031 |
| format | Article |
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cis-1,2-diaminocyclohexane bearing a third ring substituent. Starting from 3-cyclohexenecarboxylic acid, we developed efficient methods for synthesizing the 3,4-diaminocyclohexanecarboxylic acid derivatives
2–
5. We also evaluated their anti-Xa and anticoagulant activities. Among the compounds, acid
2a and amide
2b exhibited the most potent in vitro anti-fXa activity, indicating that the position and stereochemistry of a polar functional group on the cyclohexane ring greatly affected the in vitro anti-fXa activity.</description><identifier>ISSN: 0960-894X</identifier><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3405</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmcl.2008.07.031</identifier><identifier>PMID: 18675545</identifier><language>eng</language><publisher>Oxford: Elsevier Ltd</publisher><subject>3,4-Diaminocyclohexanecarboxylic acid ; Animals ; Anticoagulants - pharmacology ; Antithrombin III - chemistry ; Antithrombin III - pharmacology ; Benzothiazoles - chemical synthesis ; Benzothiazoles - pharmacology ; Biological and medical sciences ; Blood Coagulation - drug effects ; Blood. Blood coagulation. Reticuloendothelial system ; Carboxylic Acids - chemistry ; Carboxylic Acids - pharmacology ; Chemistry, Pharmaceutical - methods ; Cyclohexanes - chemistry ; Cyclohexylamines - chemical synthesis ; Cyclohexylamines - pharmacology ; Drug Design ; Factor Xa - chemistry ; Factor Xa Inhibitors ; Inhibitory Concentration 50 ; Medical sciences ; Models, Chemical ; Pharmacology. Drug treatments ; Serine Proteinase Inhibitors - chemical synthesis ; Stereoisomerism ; Stereoselective synthesis ; Time Factors</subject><ispartof>Bioorganic & medicinal chemistry, 2008-08, Vol.18 (16), p.4587-4592</ispartof><rights>2008 Elsevier Ltd</rights><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c415t-635bc3528c2cbf1f8aafd84c83330c36ec58e155b81cf8b00b1de69f0e87e3733</citedby><cites>FETCH-LOGICAL-c415t-635bc3528c2cbf1f8aafd84c83330c36ec58e155b81cf8b00b1de69f0e87e3733</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2008.07.031$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20608604$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18675545$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nagata, Tsutomu</creatorcontrib><creatorcontrib>Nagamochi, Masatoshi</creatorcontrib><creatorcontrib>Kobayashi, Shozo</creatorcontrib><creatorcontrib>Komoriya, Satoshi</creatorcontrib><creatorcontrib>Yoshino, Toshiharu</creatorcontrib><creatorcontrib>Kanno, Hideyuki</creatorcontrib><title>Stereoselective synthesis and biological evaluation of 3,4-diaminocyclohexanecarboxylic acid derivatives as factor Xa inhibitors</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem Lett</addtitle><description>There have been few reports on synthetic methods for
cis-1,2-diaminocyclohexane bearing a third ring substituent. Starting from 3-cyclohexenecarboxylic acid, we developed efficient methods for synthesizing the 3,4-diaminocyclohexanecarboxylic acid derivatives
2–
5. We also evaluated their anti-Xa and anticoagulant activities. Among the compounds, acid
2a and amide
2b exhibited the most potent in vitro anti-fXa activity, indicating that the position and stereochemistry of a polar functional group on the cyclohexane ring greatly affected the in vitro anti-fXa activity.</description><subject>3,4-Diaminocyclohexanecarboxylic acid</subject><subject>Animals</subject><subject>Anticoagulants - pharmacology</subject><subject>Antithrombin III - chemistry</subject><subject>Antithrombin III - pharmacology</subject><subject>Benzothiazoles - chemical synthesis</subject><subject>Benzothiazoles - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Blood Coagulation - drug effects</subject><subject>Blood. Blood coagulation. Reticuloendothelial system</subject><subject>Carboxylic Acids - chemistry</subject><subject>Carboxylic Acids - pharmacology</subject><subject>Chemistry, Pharmaceutical - methods</subject><subject>Cyclohexanes - chemistry</subject><subject>Cyclohexylamines - chemical synthesis</subject><subject>Cyclohexylamines - pharmacology</subject><subject>Drug Design</subject><subject>Factor Xa - chemistry</subject><subject>Factor Xa Inhibitors</subject><subject>Inhibitory Concentration 50</subject><subject>Medical sciences</subject><subject>Models, Chemical</subject><subject>Pharmacology. Drug treatments</subject><subject>Serine Proteinase Inhibitors - chemical synthesis</subject><subject>Stereoisomerism</subject><subject>Stereoselective synthesis</subject><subject>Time Factors</subject><issn>0960-894X</issn><issn>0968-0896</issn><issn>1464-3405</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kcGKFDEQhhtR3NnVF_AguejJbiudpDsDXpZFV2HBgwp7C0l1xcnQ3VmTnmHn5qObYQa9eSoKvv-n-KqqXnFoOPDu_bZxE45NC6Ab6BsQ_Em14rKTtZCgnlYrWHdQ67W8v6guc94CcAlSPq8uuO56paRaVb-_LZQoZhoJl7Anlg_zsqEcMrPzwFyIY_wZ0I6M9nbc2SXEmUXPxDtZD8FOYY54wDFu6NHOhDa5-HgYAzKLYWADpbC3x95Sl5m3uMTE7i0L8ya4UJb8onrm7Zjp5XleVT8-ffx-87m--3r75eb6rkbJ1VJ3QjkUqtXYovPca2v9oCVqIQSg6AiVJq6U0xy9dgCOD9StPZDuSfRCXFVvT70PKf7aUV7MFDLSOJaz4y4bvhaCa1AFbE8gpphzIm8eUphsOhgO5ujdbM3Ruzl6N9Cb4r2EXp_bd26i4V_kLLoAb86AzcWmT3bGkP9yLXSgO5CF-3DiqLjYB0omY6AZaQipfMgMMfzvjj8r1qRs</recordid><startdate>20080815</startdate><enddate>20080815</enddate><creator>Nagata, Tsutomu</creator><creator>Nagamochi, Masatoshi</creator><creator>Kobayashi, Shozo</creator><creator>Komoriya, Satoshi</creator><creator>Yoshino, Toshiharu</creator><creator>Kanno, Hideyuki</creator><general>Elsevier Ltd</general><general>Elsevier</general><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>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20080815</creationdate><title>Stereoselective synthesis and biological evaluation of 3,4-diaminocyclohexanecarboxylic acid derivatives as factor Xa inhibitors</title><author>Nagata, Tsutomu ; Nagamochi, Masatoshi ; Kobayashi, Shozo ; Komoriya, Satoshi ; Yoshino, Toshiharu ; Kanno, Hideyuki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c415t-635bc3528c2cbf1f8aafd84c83330c36ec58e155b81cf8b00b1de69f0e87e3733</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>3,4-Diaminocyclohexanecarboxylic acid</topic><topic>Animals</topic><topic>Anticoagulants - pharmacology</topic><topic>Antithrombin III - chemistry</topic><topic>Antithrombin III - pharmacology</topic><topic>Benzothiazoles - chemical synthesis</topic><topic>Benzothiazoles - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Blood Coagulation - drug effects</topic><topic>Blood. Blood coagulation. Reticuloendothelial system</topic><topic>Carboxylic Acids - chemistry</topic><topic>Carboxylic Acids - pharmacology</topic><topic>Chemistry, Pharmaceutical - methods</topic><topic>Cyclohexanes - chemistry</topic><topic>Cyclohexylamines - chemical synthesis</topic><topic>Cyclohexylamines - pharmacology</topic><topic>Drug Design</topic><topic>Factor Xa - chemistry</topic><topic>Factor Xa Inhibitors</topic><topic>Inhibitory Concentration 50</topic><topic>Medical sciences</topic><topic>Models, Chemical</topic><topic>Pharmacology. Drug treatments</topic><topic>Serine Proteinase Inhibitors - chemical synthesis</topic><topic>Stereoisomerism</topic><topic>Stereoselective synthesis</topic><topic>Time Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nagata, Tsutomu</creatorcontrib><creatorcontrib>Nagamochi, Masatoshi</creatorcontrib><creatorcontrib>Kobayashi, Shozo</creatorcontrib><creatorcontrib>Komoriya, Satoshi</creatorcontrib><creatorcontrib>Yoshino, Toshiharu</creatorcontrib><creatorcontrib>Kanno, Hideyuki</creatorcontrib><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>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nagata, Tsutomu</au><au>Nagamochi, Masatoshi</au><au>Kobayashi, Shozo</au><au>Komoriya, Satoshi</au><au>Yoshino, Toshiharu</au><au>Kanno, Hideyuki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Stereoselective synthesis and biological evaluation of 3,4-diaminocyclohexanecarboxylic acid derivatives as factor Xa inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2008-08-15</date><risdate>2008</risdate><volume>18</volume><issue>16</issue><spage>4587</spage><epage>4592</epage><pages>4587-4592</pages><issn>0960-894X</issn><issn>0968-0896</issn><eissn>1464-3405</eissn><eissn>1464-3391</eissn><abstract>There have been few reports on synthetic methods for
cis-1,2-diaminocyclohexane bearing a third ring substituent. Starting from 3-cyclohexenecarboxylic acid, we developed efficient methods for synthesizing the 3,4-diaminocyclohexanecarboxylic acid derivatives
2–
5. We also evaluated their anti-Xa and anticoagulant activities. Among the compounds, acid
2a and amide
2b exhibited the most potent in vitro anti-fXa activity, indicating that the position and stereochemistry of a polar functional group on the cyclohexane ring greatly affected the in vitro anti-fXa activity.</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>18675545</pmid><doi>10.1016/j.bmcl.2008.07.031</doi><tpages>6</tpages></addata></record> |
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| subjects | 3,4-Diaminocyclohexanecarboxylic acid Animals Anticoagulants - pharmacology Antithrombin III - chemistry Antithrombin III - pharmacology Benzothiazoles - chemical synthesis Benzothiazoles - pharmacology Biological and medical sciences Blood Coagulation - drug effects Blood. Blood coagulation. Reticuloendothelial system Carboxylic Acids - chemistry Carboxylic Acids - pharmacology Chemistry, Pharmaceutical - methods Cyclohexanes - chemistry Cyclohexylamines - chemical synthesis Cyclohexylamines - pharmacology Drug Design Factor Xa - chemistry Factor Xa Inhibitors Inhibitory Concentration 50 Medical sciences Models, Chemical Pharmacology. Drug treatments Serine Proteinase Inhibitors - chemical synthesis Stereoisomerism Stereoselective synthesis Time Factors |
| title | Stereoselective synthesis and biological evaluation of 3,4-diaminocyclohexanecarboxylic acid derivatives as factor Xa inhibitors |
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