1,4-Cyclohexanecarboxylates: Potent and Selective Inhibitors of Phosophodiesterase 4 for the Treatment of Asthma
Evaluation of a variety of PDE4 inhibitors in a series of cellular and in vivo assays suggested a strategy to improve the therapeutic index of PDE4 inhibitors by increasing their selectivity for the ability to inhibit PDE4 catalytic activity versus the ability to compete for high affinity [3H]rolipr...
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| Veröffentlicht in: | Journal of medicinal chemistry 1998-03, Vol.41 (6), p.821-835 |
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| container_title | Journal of medicinal chemistry |
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| creator | Christensen, Siegfried B Guider, Aimee Forster, Cornelia J Gleason, John G Bender, Paul E Karpinski, Joseph M DeWolf, Walter E Barnette, Mary S Underwood, David C Griswold, Don E Cieslinski, Lenora B Burman, Miriam Bochnowicz, Steven Osborn, Ruth R Manning, Carol D Grous, Marilyn Hillegas, Leonard M Bartus, Joan O'Leary Ryan, M. Dominic Eggleston, Drake S Haltiwanger, R. Curtis Torphy, Theodore J |
| description | Evaluation of a variety of PDE4 inhibitors in a series of cellular and in vivo assays suggested a strategy to improve the therapeutic index of PDE4 inhibitors by increasing their selectivity for the ability to inhibit PDE4 catalytic activity versus the ability to compete for high affinity [3H]rolipram-binding sites in the central nervous system. Use of this strategy led ultimately to the identification of cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylic acid (1, SB 207499, ArifloTM), a potent second-generation inhibitor of PDE4 with a decreased potential for side effects versus the archetypic first generation inhibitor, (R)-rolipram. |
| doi_str_mv | 10.1021/jm970090r |
| format | Article |
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Dominic ; Eggleston, Drake S ; Haltiwanger, R. Curtis ; Torphy, Theodore J</creator><creatorcontrib>Christensen, Siegfried B ; Guider, Aimee ; Forster, Cornelia J ; Gleason, John G ; Bender, Paul E ; Karpinski, Joseph M ; DeWolf, Walter E ; Barnette, Mary S ; Underwood, David C ; Griswold, Don E ; Cieslinski, Lenora B ; Burman, Miriam ; Bochnowicz, Steven ; Osborn, Ruth R ; Manning, Carol D ; Grous, Marilyn ; Hillegas, Leonard M ; Bartus, Joan O'Leary ; Ryan, M. Dominic ; Eggleston, Drake S ; Haltiwanger, R. Curtis ; Torphy, Theodore J</creatorcontrib><description>Evaluation of a variety of PDE4 inhibitors in a series of cellular and in vivo assays suggested a strategy to improve the therapeutic index of PDE4 inhibitors by increasing their selectivity for the ability to inhibit PDE4 catalytic activity versus the ability to compete for high affinity [3H]rolipram-binding sites in the central nervous system. Use of this strategy led ultimately to the identification of cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylic acid (1, SB 207499, ArifloTM), a potent second-generation inhibitor of PDE4 with a decreased potential for side effects versus the archetypic first generation inhibitor, (R)-rolipram.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm970090r</identifier><identifier>PMID: 9526558</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors ; Animals ; Anti-Asthmatic Agents - chemical synthesis ; Anti-Asthmatic Agents - metabolism ; Anti-Asthmatic Agents - pharmacology ; Anti-Asthmatic Agents - toxicity ; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis ; Anti-Inflammatory Agents, Non-Steroidal - metabolism ; Anti-Inflammatory Agents, Non-Steroidal - pharmacology ; Anti-Inflammatory Agents, Non-Steroidal - toxicity ; Binding, Competitive ; Biological and medical sciences ; Body Temperature - drug effects ; Brain - metabolism ; Bronchoconstriction - drug effects ; Cyclic Nucleotide Phosphodiesterases, Type 4 ; Cyclohexanecarboxylic Acids - chemical synthesis ; Cyclohexanecarboxylic Acids - metabolism ; Cyclohexanecarboxylic Acids - pharmacology ; Cyclohexanecarboxylic Acids - toxicity ; Dogs ; Gastric Acid - secretion ; Guinea Pigs ; Humans ; Medical sciences ; Mice ; Monocytes - drug effects ; Monocytes - metabolism ; Nitriles ; Pharmacology. Drug treatments ; Phosphodiesterase Inhibitors - chemical synthesis ; Phosphodiesterase Inhibitors - metabolism ; Phosphodiesterase Inhibitors - pharmacology ; Phosphodiesterase Inhibitors - toxicity ; Pyrrolidinones - chemical synthesis ; Pyrrolidinones - metabolism ; Pyrrolidinones - pharmacology ; Pyrrolidinones - toxicity ; Rabbits ; Recombinant Proteins - antagonists & inhibitors ; Respiratory system ; Rolipram ; Stereoisomerism ; Structure-Activity Relationship ; Tumor Necrosis Factor-alpha - antagonists & inhibitors ; Vomiting - chemically induced</subject><ispartof>Journal of medicinal chemistry, 1998-03, Vol.41 (6), p.821-835</ispartof><rights>Copyright © 1998 American Chemical Society</rights><rights>1998 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a360t-b70fde73064091ba66ef7644c46e1b42c5a90a26c4e1909134f52a9a62d8225b3</citedby><cites>FETCH-LOGICAL-a360t-b70fde73064091ba66ef7644c46e1b42c5a90a26c4e1909134f52a9a62d8225b3</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/jm970090r$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm970090r$$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=2201039$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9526558$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Christensen, Siegfried B</creatorcontrib><creatorcontrib>Guider, Aimee</creatorcontrib><creatorcontrib>Forster, Cornelia J</creatorcontrib><creatorcontrib>Gleason, John G</creatorcontrib><creatorcontrib>Bender, Paul E</creatorcontrib><creatorcontrib>Karpinski, Joseph M</creatorcontrib><creatorcontrib>DeWolf, Walter E</creatorcontrib><creatorcontrib>Barnette, Mary S</creatorcontrib><creatorcontrib>Underwood, David C</creatorcontrib><creatorcontrib>Griswold, Don E</creatorcontrib><creatorcontrib>Cieslinski, Lenora B</creatorcontrib><creatorcontrib>Burman, Miriam</creatorcontrib><creatorcontrib>Bochnowicz, Steven</creatorcontrib><creatorcontrib>Osborn, Ruth R</creatorcontrib><creatorcontrib>Manning, Carol D</creatorcontrib><creatorcontrib>Grous, Marilyn</creatorcontrib><creatorcontrib>Hillegas, Leonard M</creatorcontrib><creatorcontrib>Bartus, Joan O'Leary</creatorcontrib><creatorcontrib>Ryan, M. Dominic</creatorcontrib><creatorcontrib>Eggleston, Drake S</creatorcontrib><creatorcontrib>Haltiwanger, R. Curtis</creatorcontrib><creatorcontrib>Torphy, Theodore J</creatorcontrib><title>1,4-Cyclohexanecarboxylates: Potent and Selective Inhibitors of Phosophodiesterase 4 for the Treatment of Asthma</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Evaluation of a variety of PDE4 inhibitors in a series of cellular and in vivo assays suggested a strategy to improve the therapeutic index of PDE4 inhibitors by increasing their selectivity for the ability to inhibit PDE4 catalytic activity versus the ability to compete for high affinity [3H]rolipram-binding sites in the central nervous system. Use of this strategy led ultimately to the identification of cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylic acid (1, SB 207499, ArifloTM), a potent second-generation inhibitor of PDE4 with a decreased potential for side effects versus the archetypic first generation inhibitor, (R)-rolipram.</description><subject>3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors</subject><subject>Animals</subject><subject>Anti-Asthmatic Agents - chemical synthesis</subject><subject>Anti-Asthmatic Agents - metabolism</subject><subject>Anti-Asthmatic Agents - pharmacology</subject><subject>Anti-Asthmatic Agents - toxicity</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - metabolism</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - toxicity</subject><subject>Binding, Competitive</subject><subject>Biological and medical sciences</subject><subject>Body Temperature - drug effects</subject><subject>Brain - metabolism</subject><subject>Bronchoconstriction - drug effects</subject><subject>Cyclic Nucleotide Phosphodiesterases, Type 4</subject><subject>Cyclohexanecarboxylic Acids - chemical synthesis</subject><subject>Cyclohexanecarboxylic Acids - metabolism</subject><subject>Cyclohexanecarboxylic Acids - pharmacology</subject><subject>Cyclohexanecarboxylic Acids - toxicity</subject><subject>Dogs</subject><subject>Gastric Acid - secretion</subject><subject>Guinea Pigs</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Monocytes - drug effects</subject><subject>Monocytes - metabolism</subject><subject>Nitriles</subject><subject>Pharmacology. Drug treatments</subject><subject>Phosphodiesterase Inhibitors - chemical synthesis</subject><subject>Phosphodiesterase Inhibitors - metabolism</subject><subject>Phosphodiesterase Inhibitors - pharmacology</subject><subject>Phosphodiesterase Inhibitors - toxicity</subject><subject>Pyrrolidinones - chemical synthesis</subject><subject>Pyrrolidinones - metabolism</subject><subject>Pyrrolidinones - pharmacology</subject><subject>Pyrrolidinones - toxicity</subject><subject>Rabbits</subject><subject>Recombinant Proteins - antagonists & inhibitors</subject><subject>Respiratory system</subject><subject>Rolipram</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><subject>Tumor Necrosis Factor-alpha - antagonists & inhibitors</subject><subject>Vomiting - chemically induced</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>eNpt0E9v0zAYx3ELgUa3ceAFIPkAh0kEHv-J03Cbqm1MmkTFOg5crCfOEyUliSvbm9obV94mr4RMrXri5MPvo0fWl7G3Aj4JkOLzeigLgBLCCzYTuYRMz0G_ZDMAKTNppHrNTmNcA4ASUp2wkzKXJs_nMxbFR50tdq73LW1xJIeh8ttdj4nil7-___ClTzQmjmPN76knl7on4rdj21Vd8iFy3_Bl66PftL7uKCYKGIlr3vjAU0t8FQjT8HxikpcxtQOes1cN9pHeHN4z9nB9tVp8ze6-3dwuLu8yVAZSVhXQ1FQoMBpKUaEx1BRGa6cNiUpLl2MJKI3TJMpJKN3kEks0sp5LmVfqjF3s77rgYwzU2E3oBgw7K8A-d7PHbpN9t7ebx2qg-igPoab9_WHH6LBvAo6ui0cmJQhQ5cSyPeumEtvjjOGXNYUqcrta3lv4sZjfXH__acXkP-w9umjX_jGMU5D_fO8f9VSRRw</recordid><startdate>19980312</startdate><enddate>19980312</enddate><creator>Christensen, Siegfried B</creator><creator>Guider, Aimee</creator><creator>Forster, Cornelia J</creator><creator>Gleason, John G</creator><creator>Bender, Paul E</creator><creator>Karpinski, Joseph M</creator><creator>DeWolf, Walter E</creator><creator>Barnette, Mary S</creator><creator>Underwood, David C</creator><creator>Griswold, Don E</creator><creator>Cieslinski, Lenora B</creator><creator>Burman, Miriam</creator><creator>Bochnowicz, Steven</creator><creator>Osborn, Ruth R</creator><creator>Manning, Carol D</creator><creator>Grous, Marilyn</creator><creator>Hillegas, Leonard M</creator><creator>Bartus, Joan O'Leary</creator><creator>Ryan, M. Dominic</creator><creator>Eggleston, Drake S</creator><creator>Haltiwanger, R. Curtis</creator><creator>Torphy, Theodore J</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></search><sort><creationdate>19980312</creationdate><title>1,4-Cyclohexanecarboxylates: Potent and Selective Inhibitors of Phosophodiesterase 4 for the Treatment of Asthma</title><author>Christensen, Siegfried B ; Guider, Aimee ; Forster, Cornelia J ; Gleason, John G ; Bender, Paul E ; Karpinski, Joseph M ; DeWolf, Walter E ; Barnette, Mary S ; Underwood, David C ; Griswold, Don E ; Cieslinski, Lenora B ; Burman, Miriam ; Bochnowicz, Steven ; Osborn, Ruth R ; Manning, Carol D ; Grous, Marilyn ; Hillegas, Leonard M ; Bartus, Joan O'Leary ; Ryan, M. Dominic ; Eggleston, Drake S ; Haltiwanger, R. Curtis ; Torphy, Theodore J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a360t-b70fde73064091ba66ef7644c46e1b42c5a90a26c4e1909134f52a9a62d8225b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1998</creationdate><topic>3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors</topic><topic>Animals</topic><topic>Anti-Asthmatic Agents - chemical synthesis</topic><topic>Anti-Asthmatic Agents - metabolism</topic><topic>Anti-Asthmatic Agents - pharmacology</topic><topic>Anti-Asthmatic Agents - toxicity</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - metabolism</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - toxicity</topic><topic>Binding, Competitive</topic><topic>Biological and medical sciences</topic><topic>Body Temperature - drug effects</topic><topic>Brain - metabolism</topic><topic>Bronchoconstriction - drug effects</topic><topic>Cyclic Nucleotide Phosphodiesterases, Type 4</topic><topic>Cyclohexanecarboxylic Acids - chemical synthesis</topic><topic>Cyclohexanecarboxylic Acids - metabolism</topic><topic>Cyclohexanecarboxylic Acids - pharmacology</topic><topic>Cyclohexanecarboxylic Acids - toxicity</topic><topic>Dogs</topic><topic>Gastric Acid - secretion</topic><topic>Guinea Pigs</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Monocytes - drug effects</topic><topic>Monocytes - metabolism</topic><topic>Nitriles</topic><topic>Pharmacology. Drug treatments</topic><topic>Phosphodiesterase Inhibitors - chemical synthesis</topic><topic>Phosphodiesterase Inhibitors - metabolism</topic><topic>Phosphodiesterase Inhibitors - pharmacology</topic><topic>Phosphodiesterase Inhibitors - toxicity</topic><topic>Pyrrolidinones - chemical synthesis</topic><topic>Pyrrolidinones - metabolism</topic><topic>Pyrrolidinones - pharmacology</topic><topic>Pyrrolidinones - toxicity</topic><topic>Rabbits</topic><topic>Recombinant Proteins - antagonists & inhibitors</topic><topic>Respiratory system</topic><topic>Rolipram</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><topic>Tumor Necrosis Factor-alpha - antagonists & inhibitors</topic><topic>Vomiting - chemically induced</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Christensen, Siegfried B</creatorcontrib><creatorcontrib>Guider, Aimee</creatorcontrib><creatorcontrib>Forster, Cornelia J</creatorcontrib><creatorcontrib>Gleason, John G</creatorcontrib><creatorcontrib>Bender, Paul E</creatorcontrib><creatorcontrib>Karpinski, Joseph M</creatorcontrib><creatorcontrib>DeWolf, Walter E</creatorcontrib><creatorcontrib>Barnette, Mary S</creatorcontrib><creatorcontrib>Underwood, David C</creatorcontrib><creatorcontrib>Griswold, Don E</creatorcontrib><creatorcontrib>Cieslinski, Lenora B</creatorcontrib><creatorcontrib>Burman, Miriam</creatorcontrib><creatorcontrib>Bochnowicz, Steven</creatorcontrib><creatorcontrib>Osborn, Ruth R</creatorcontrib><creatorcontrib>Manning, Carol D</creatorcontrib><creatorcontrib>Grous, Marilyn</creatorcontrib><creatorcontrib>Hillegas, Leonard M</creatorcontrib><creatorcontrib>Bartus, Joan O'Leary</creatorcontrib><creatorcontrib>Ryan, M. 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Use of this strategy led ultimately to the identification of cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylic acid (1, SB 207499, ArifloTM), a potent second-generation inhibitor of PDE4 with a decreased potential for side effects versus the archetypic first generation inhibitor, (R)-rolipram.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>9526558</pmid><doi>10.1021/jm970090r</doi><tpages>15</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 1998-03, Vol.41 (6), p.821-835 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_crossref_primary_10_1021_jm970090r |
| source | MEDLINE; ACS Journals: American Chemical Society Web Editions |
| subjects | 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors Animals Anti-Asthmatic Agents - chemical synthesis Anti-Asthmatic Agents - metabolism Anti-Asthmatic Agents - pharmacology Anti-Asthmatic Agents - toxicity Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis Anti-Inflammatory Agents, Non-Steroidal - metabolism Anti-Inflammatory Agents, Non-Steroidal - pharmacology Anti-Inflammatory Agents, Non-Steroidal - toxicity Binding, Competitive Biological and medical sciences Body Temperature - drug effects Brain - metabolism Bronchoconstriction - drug effects Cyclic Nucleotide Phosphodiesterases, Type 4 Cyclohexanecarboxylic Acids - chemical synthesis Cyclohexanecarboxylic Acids - metabolism Cyclohexanecarboxylic Acids - pharmacology Cyclohexanecarboxylic Acids - toxicity Dogs Gastric Acid - secretion Guinea Pigs Humans Medical sciences Mice Monocytes - drug effects Monocytes - metabolism Nitriles Pharmacology. Drug treatments Phosphodiesterase Inhibitors - chemical synthesis Phosphodiesterase Inhibitors - metabolism Phosphodiesterase Inhibitors - pharmacology Phosphodiesterase Inhibitors - toxicity Pyrrolidinones - chemical synthesis Pyrrolidinones - metabolism Pyrrolidinones - pharmacology Pyrrolidinones - toxicity Rabbits Recombinant Proteins - antagonists & inhibitors Respiratory system Rolipram Stereoisomerism Structure-Activity Relationship Tumor Necrosis Factor-alpha - antagonists & inhibitors Vomiting - chemically induced |
| title | 1,4-Cyclohexanecarboxylates: Potent and Selective Inhibitors of Phosophodiesterase 4 for the Treatment of Asthma |
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