Synthesis and Biological Evaluation of Novel Pyrazoles and Indazoles as Activators of the Nitric Oxide Receptor, Soluble Guanylate Cyclase
Database searching and compound screening identified 1-benzyl-3-(3-dimethylaminopropyloxy)indazole (benzydamine, 3) as a potent activator of the nitric oxide receptor, soluble guanylate cyclase. A comprehensive structure−activity relationship study surrounding 3 clearly showed that the indazole C-3...
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| Veröffentlicht in: | Journal of medicinal chemistry 2001-01, Vol.44 (1), p.78-93 |
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| creator | Selwood, David L Brummell, David G Budworth, Joanna Burtin, Guillaume E Campbell, Richard O Chana, Surinder S Charles, Ian G Fernandez, Patricia A Glen, Robert C Goggin, Maria C Hobbs, Adrian J Kling, Marcel R Liu, Qian Madge, David J Meillerais, Sylvie Powell, Kenneth L Reynolds, Karen Spacey, Graham D Stables, Jeremy N Tatlock, Mark A Wheeler, Kerry A Wishart, Grant Woo, Chi-Kit |
| description | Database searching and compound screening identified 1-benzyl-3-(3-dimethylaminopropyloxy)indazole (benzydamine, 3) as a potent activator of the nitric oxide receptor, soluble guanylate cyclase. A comprehensive structure−activity relationship study surrounding 3 clearly showed that the indazole C-3 dimethylaminopropyloxy substituent was critical for enzyme activity. However replacement of the indazole ring of 3 by appropriately substituted pyrazoles maintained enzyme activity. Compounds were evaluated for inhibition of platelet aggregation and showed a general lipophilicity requirement. Aryl-substituted pyrazoles 32, 34, and 43 demonstrated potent activation of soluble guanylate cyclase and potent inhibition of platelet aggregation. Pharmacokinetic studies in rats showed that compound 32 exhibits modest oral bioavailability (12%). Furthermore 32 has an excellent selectivity profile notably showing no significant inhibition of phosphodiesterases or nitric oxide synthases. |
| doi_str_mv | 10.1021/jm001034k |
| format | Article |
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A comprehensive structure−activity relationship study surrounding 3 clearly showed that the indazole C-3 dimethylaminopropyloxy substituent was critical for enzyme activity. However replacement of the indazole ring of 3 by appropriately substituted pyrazoles maintained enzyme activity. Compounds were evaluated for inhibition of platelet aggregation and showed a general lipophilicity requirement. Aryl-substituted pyrazoles 32, 34, and 43 demonstrated potent activation of soluble guanylate cyclase and potent inhibition of platelet aggregation. Pharmacokinetic studies in rats showed that compound 32 exhibits modest oral bioavailability (12%). Furthermore 32 has an excellent selectivity profile notably showing no significant inhibition of phosphodiesterases or nitric oxide synthases.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm001034k</identifier><identifier>PMID: 11141091</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Biological and medical sciences ; Blood. Blood coagulation. Reticuloendothelial system ; Enzyme Activation ; Guanylate Cyclase - metabolism ; Humans ; In Vitro Techniques ; Indazoles - chemical synthesis ; Indazoles - chemistry ; Indazoles - pharmacokinetics ; Indazoles - pharmacology ; Male ; Medical sciences ; Nitric Oxide - metabolism ; Pharmacology. Drug treatments ; Platelet Aggregation Inhibitors - chemical synthesis ; Platelet Aggregation Inhibitors - chemistry ; Platelet Aggregation Inhibitors - pharmacokinetics ; Platelet Aggregation Inhibitors - pharmacology ; Pyrazoles - chemical synthesis ; Pyrazoles - chemistry ; Pyrazoles - pharmacokinetics ; Pyrazoles - pharmacology ; Rats ; Rats, Sprague-Dawley ; Solubility ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2001-01, Vol.44 (1), p.78-93</ispartof><rights>Copyright © 2001 American Chemical Society</rights><rights>2001 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a468t-914e5a10d0d23f75a609d75d6d89fe56d513baecbc9ec3cd1a88ae7379e70b6a3</citedby><cites>FETCH-LOGICAL-a468t-914e5a10d0d23f75a609d75d6d89fe56d513baecbc9ec3cd1a88ae7379e70b6a3</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/jm001034k$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm001034k$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,777,781,2752,27057,27905,27906,56719,56769</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=867452$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11141091$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Selwood, David L</creatorcontrib><creatorcontrib>Brummell, David G</creatorcontrib><creatorcontrib>Budworth, Joanna</creatorcontrib><creatorcontrib>Burtin, Guillaume E</creatorcontrib><creatorcontrib>Campbell, Richard O</creatorcontrib><creatorcontrib>Chana, Surinder S</creatorcontrib><creatorcontrib>Charles, Ian G</creatorcontrib><creatorcontrib>Fernandez, Patricia A</creatorcontrib><creatorcontrib>Glen, Robert C</creatorcontrib><creatorcontrib>Goggin, Maria C</creatorcontrib><creatorcontrib>Hobbs, Adrian J</creatorcontrib><creatorcontrib>Kling, Marcel R</creatorcontrib><creatorcontrib>Liu, Qian</creatorcontrib><creatorcontrib>Madge, David J</creatorcontrib><creatorcontrib>Meillerais, Sylvie</creatorcontrib><creatorcontrib>Powell, Kenneth L</creatorcontrib><creatorcontrib>Reynolds, Karen</creatorcontrib><creatorcontrib>Spacey, Graham D</creatorcontrib><creatorcontrib>Stables, Jeremy N</creatorcontrib><creatorcontrib>Tatlock, Mark A</creatorcontrib><creatorcontrib>Wheeler, Kerry A</creatorcontrib><creatorcontrib>Wishart, Grant</creatorcontrib><creatorcontrib>Woo, Chi-Kit</creatorcontrib><title>Synthesis and Biological Evaluation of Novel Pyrazoles and Indazoles as Activators of the Nitric Oxide Receptor, Soluble Guanylate Cyclase</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Database searching and compound screening identified 1-benzyl-3-(3-dimethylaminopropyloxy)indazole (benzydamine, 3) as a potent activator of the nitric oxide receptor, soluble guanylate cyclase. A comprehensive structure−activity relationship study surrounding 3 clearly showed that the indazole C-3 dimethylaminopropyloxy substituent was critical for enzyme activity. However replacement of the indazole ring of 3 by appropriately substituted pyrazoles maintained enzyme activity. Compounds were evaluated for inhibition of platelet aggregation and showed a general lipophilicity requirement. Aryl-substituted pyrazoles 32, 34, and 43 demonstrated potent activation of soluble guanylate cyclase and potent inhibition of platelet aggregation. Pharmacokinetic studies in rats showed that compound 32 exhibits modest oral bioavailability (12%). Furthermore 32 has an excellent selectivity profile notably showing no significant inhibition of phosphodiesterases or nitric oxide synthases.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Blood. Blood coagulation. Reticuloendothelial system</subject><subject>Enzyme Activation</subject><subject>Guanylate Cyclase - metabolism</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Indazoles - chemical synthesis</subject><subject>Indazoles - chemistry</subject><subject>Indazoles - pharmacokinetics</subject><subject>Indazoles - pharmacology</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Nitric Oxide - metabolism</subject><subject>Pharmacology. Drug treatments</subject><subject>Platelet Aggregation Inhibitors - chemical synthesis</subject><subject>Platelet Aggregation Inhibitors - chemistry</subject><subject>Platelet Aggregation Inhibitors - pharmacokinetics</subject><subject>Platelet Aggregation Inhibitors - pharmacology</subject><subject>Pyrazoles - chemical synthesis</subject><subject>Pyrazoles - chemistry</subject><subject>Pyrazoles - pharmacokinetics</subject><subject>Pyrazoles - pharmacology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Solubility</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0NFu0zAUBmALgVgZXPACyBICaRIB20mc5HKrtjFpbIMOcWmd2ifgzo2LnVQLj8BT4yml3HBlW-fTL5-fkJecvedM8A-rNWOc5cXdIzLjpWBZUbPiMZkxJkQmpMgPyLMYV4yxnIv8KTngnBecNXxGfi_Grv-B0UYKnaEn1jv_3Wpw9HQLboDe-o76ll75LTp6Mwb45R1O-KIzf1-RHuvebqH3IT7wFEmvbB-sptf31iD9gho3afqOLrwblg7p-QDd6KBHOh-1g4jPyZMWXMQXu_OQfD07vZ1_zC6vzy_mx5cZFLLus4YXWAJnhhmRt1UJkjWmKo00ddNiKU3J8yWgXuoGda4Nh7oGrPKqwYotJeSH5O2Uuwn-54CxV2sbNToHHfohqoqVkleNTPBogjr4GAO2ahPsGsKoOFMPxat98cm-2oUOyzWaf3LXdAKvdwBiqrcN0Gkb966WVVGKpLJJ2djj_X4K4U7JtEKpbm8W6pv4fFKwT-mS_JvJg45q5YfQpeb-870_-3WnoA</recordid><startdate>20010104</startdate><enddate>20010104</enddate><creator>Selwood, David L</creator><creator>Brummell, David G</creator><creator>Budworth, Joanna</creator><creator>Burtin, Guillaume E</creator><creator>Campbell, Richard O</creator><creator>Chana, Surinder S</creator><creator>Charles, Ian G</creator><creator>Fernandez, Patricia A</creator><creator>Glen, Robert C</creator><creator>Goggin, Maria C</creator><creator>Hobbs, Adrian J</creator><creator>Kling, Marcel R</creator><creator>Liu, Qian</creator><creator>Madge, David J</creator><creator>Meillerais, Sylvie</creator><creator>Powell, Kenneth L</creator><creator>Reynolds, Karen</creator><creator>Spacey, Graham D</creator><creator>Stables, Jeremy N</creator><creator>Tatlock, Mark A</creator><creator>Wheeler, Kerry A</creator><creator>Wishart, Grant</creator><creator>Woo, Chi-Kit</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>20010104</creationdate><title>Synthesis and Biological Evaluation of Novel Pyrazoles and Indazoles as Activators of the Nitric Oxide Receptor, Soluble Guanylate Cyclase</title><author>Selwood, David L ; Brummell, David G ; Budworth, Joanna ; Burtin, Guillaume E ; Campbell, Richard O ; Chana, Surinder S ; Charles, Ian G ; Fernandez, Patricia A ; Glen, Robert C ; Goggin, Maria C ; Hobbs, Adrian J ; Kling, Marcel R ; Liu, Qian ; Madge, David J ; Meillerais, Sylvie ; Powell, Kenneth L ; Reynolds, Karen ; Spacey, Graham D ; Stables, Jeremy N ; Tatlock, Mark A ; Wheeler, Kerry A ; Wishart, Grant ; Woo, Chi-Kit</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a468t-914e5a10d0d23f75a609d75d6d89fe56d513baecbc9ec3cd1a88ae7379e70b6a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Blood. Blood coagulation. Reticuloendothelial system</topic><topic>Enzyme Activation</topic><topic>Guanylate Cyclase - metabolism</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Indazoles - chemical synthesis</topic><topic>Indazoles - chemistry</topic><topic>Indazoles - pharmacokinetics</topic><topic>Indazoles - pharmacology</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Nitric Oxide - metabolism</topic><topic>Pharmacology. Drug treatments</topic><topic>Platelet Aggregation Inhibitors - chemical synthesis</topic><topic>Platelet Aggregation Inhibitors - chemistry</topic><topic>Platelet Aggregation Inhibitors - pharmacokinetics</topic><topic>Platelet Aggregation Inhibitors - pharmacology</topic><topic>Pyrazoles - chemical synthesis</topic><topic>Pyrazoles - chemistry</topic><topic>Pyrazoles - pharmacokinetics</topic><topic>Pyrazoles - pharmacology</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Solubility</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Selwood, David L</creatorcontrib><creatorcontrib>Brummell, David G</creatorcontrib><creatorcontrib>Budworth, Joanna</creatorcontrib><creatorcontrib>Burtin, Guillaume E</creatorcontrib><creatorcontrib>Campbell, Richard O</creatorcontrib><creatorcontrib>Chana, Surinder S</creatorcontrib><creatorcontrib>Charles, Ian G</creatorcontrib><creatorcontrib>Fernandez, Patricia A</creatorcontrib><creatorcontrib>Glen, Robert C</creatorcontrib><creatorcontrib>Goggin, Maria C</creatorcontrib><creatorcontrib>Hobbs, Adrian J</creatorcontrib><creatorcontrib>Kling, Marcel R</creatorcontrib><creatorcontrib>Liu, Qian</creatorcontrib><creatorcontrib>Madge, David J</creatorcontrib><creatorcontrib>Meillerais, Sylvie</creatorcontrib><creatorcontrib>Powell, Kenneth L</creatorcontrib><creatorcontrib>Reynolds, Karen</creatorcontrib><creatorcontrib>Spacey, Graham D</creatorcontrib><creatorcontrib>Stables, Jeremy N</creatorcontrib><creatorcontrib>Tatlock, Mark A</creatorcontrib><creatorcontrib>Wheeler, Kerry A</creatorcontrib><creatorcontrib>Wishart, Grant</creatorcontrib><creatorcontrib>Woo, Chi-Kit</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>Selwood, David L</au><au>Brummell, David G</au><au>Budworth, Joanna</au><au>Burtin, Guillaume E</au><au>Campbell, Richard O</au><au>Chana, Surinder S</au><au>Charles, Ian G</au><au>Fernandez, Patricia A</au><au>Glen, Robert C</au><au>Goggin, Maria C</au><au>Hobbs, Adrian J</au><au>Kling, Marcel R</au><au>Liu, Qian</au><au>Madge, David J</au><au>Meillerais, Sylvie</au><au>Powell, Kenneth L</au><au>Reynolds, Karen</au><au>Spacey, Graham D</au><au>Stables, Jeremy N</au><au>Tatlock, Mark A</au><au>Wheeler, Kerry A</au><au>Wishart, Grant</au><au>Woo, Chi-Kit</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and Biological Evaluation of Novel Pyrazoles and Indazoles as Activators of the Nitric Oxide Receptor, Soluble Guanylate Cyclase</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2001-01-04</date><risdate>2001</risdate><volume>44</volume><issue>1</issue><spage>78</spage><epage>93</epage><pages>78-93</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Database searching and compound screening identified 1-benzyl-3-(3-dimethylaminopropyloxy)indazole (benzydamine, 3) as a potent activator of the nitric oxide receptor, soluble guanylate cyclase. A comprehensive structure−activity relationship study surrounding 3 clearly showed that the indazole C-3 dimethylaminopropyloxy substituent was critical for enzyme activity. However replacement of the indazole ring of 3 by appropriately substituted pyrazoles maintained enzyme activity. Compounds were evaluated for inhibition of platelet aggregation and showed a general lipophilicity requirement. Aryl-substituted pyrazoles 32, 34, and 43 demonstrated potent activation of soluble guanylate cyclase and potent inhibition of platelet aggregation. Pharmacokinetic studies in rats showed that compound 32 exhibits modest oral bioavailability (12%). Furthermore 32 has an excellent selectivity profile notably showing no significant inhibition of phosphodiesterases or nitric oxide synthases.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>11141091</pmid><doi>10.1021/jm001034k</doi><tpages>16</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2001-01, Vol.44 (1), p.78-93 |
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| subjects | Animals Biological and medical sciences Blood. Blood coagulation. Reticuloendothelial system Enzyme Activation Guanylate Cyclase - metabolism Humans In Vitro Techniques Indazoles - chemical synthesis Indazoles - chemistry Indazoles - pharmacokinetics Indazoles - pharmacology Male Medical sciences Nitric Oxide - metabolism Pharmacology. Drug treatments Platelet Aggregation Inhibitors - chemical synthesis Platelet Aggregation Inhibitors - chemistry Platelet Aggregation Inhibitors - pharmacokinetics Platelet Aggregation Inhibitors - pharmacology Pyrazoles - chemical synthesis Pyrazoles - chemistry Pyrazoles - pharmacokinetics Pyrazoles - pharmacology Rats Rats, Sprague-Dawley Solubility Structure-Activity Relationship |
| title | Synthesis and Biological Evaluation of Novel Pyrazoles and Indazoles as Activators of the Nitric Oxide Receptor, Soluble Guanylate Cyclase |
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