Potent, nonpeptide inhibitors of human mast cell tryptase. Synthesis and biological evaluation of novel spirocyclic piperidine amide derivatives
We have explored a series of spirocyclic piperidine amide derivatives ( 5) as tryptase inhibitors. Thus, 4 (JNJ-27390467) was identified as a potent, selective tryptase inhibitor with oral efficacy in two animal models of airway inflammation (sheep and guinea pig asthma models). An X-ray co-crystal...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2008-03, Vol.18 (6), p.2114-2121 |
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| creator | Costanzo, Michael J. Yabut, Stephen C. Zhang, Han-Cheng White, Kimberley B. de Garavilla, Lawrence Wang, Yuanping Minor, Lisa K. Tounge, Brett A. Barnakov, Alexander N. Lewandowski, Frank Milligan, Cynthia Spurlino, John C. Abraham, William M. Boswell-Smith, Victoria Page, Clive P. Maryanoff, Bruce E. |
| description | We have explored a series of spirocyclic piperidine amide derivatives (
5) as tryptase inhibitors. Thus,
4 (JNJ-27390467) was identified as a potent, selective tryptase inhibitor with oral efficacy in two animal models of airway inflammation (sheep and guinea pig asthma models). An X-ray co-crystal structure of
4
·
tryptase revealed a hydrophobic pocket in the enzyme’s active site, which is induced by the phenylethynyl group and is comprised of amino acid residues from two different monomers of the tetrameric protein. |
| doi_str_mv | 10.1016/j.bmcl.2008.01.093 |
| format | Article |
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5) as tryptase inhibitors. Thus,
4 (JNJ-27390467) was identified as a potent, selective tryptase inhibitor with oral efficacy in two animal models of airway inflammation (sheep and guinea pig asthma models). An X-ray co-crystal structure of
4
·
tryptase revealed a hydrophobic pocket in the enzyme’s active site, which is induced by the phenylethynyl group and is comprised of amino acid residues from two different monomers of the tetrameric protein.</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.2008.01.093</identifier><identifier>PMID: 18272363</identifier><language>eng</language><publisher>Oxford: Elsevier Ltd</publisher><subject>Administration, Oral ; Animals ; Asthma ; Asthma - drug therapy ; Biological and medical sciences ; Biological Availability ; Chromatography, High Pressure Liquid ; Crystallography, X-Ray ; Cytochrome P-450 Enzyme Inhibitors ; Disease Models, Animal ; Dogs ; Guinea Pigs ; Humans ; Inhibitor ; Medical sciences ; Microsomes, Liver - drug effects ; Microsomes, Liver - enzymology ; Molecular Structure ; Pharmacology. Drug treatments ; Rats ; Respiratory Hypersensitivity - drug therapy ; Respiratory system ; Serine Proteinase Inhibitors - chemical synthesis ; Serine Proteinase Inhibitors - pharmacokinetics ; Serine Proteinase Inhibitors - pharmacology ; Sheep ; Spectrometry, Mass, Electrospray Ionization ; Spiro Compounds - chemical synthesis ; Spiro Compounds - pharmacokinetics ; Spiro Compounds - pharmacology ; Spiropiperidine ; Trypsin - metabolism ; Tryptase ; Tryptases - antagonists & inhibitors ; Tryptases - metabolism</subject><ispartof>Bioorganic & medicinal chemistry, 2008-03, Vol.18 (6), p.2114-2121</ispartof><rights>2008 Elsevier Ltd</rights><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c415t-6722f320ed55f4c158c6645a5e09057b4ee97d1501da584d3cadc0970643ccd03</citedby><cites>FETCH-LOGICAL-c415t-6722f320ed55f4c158c6645a5e09057b4ee97d1501da584d3cadc0970643ccd03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X08001200$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27903,27904,65309</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20217259$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18272363$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Costanzo, Michael J.</creatorcontrib><creatorcontrib>Yabut, Stephen C.</creatorcontrib><creatorcontrib>Zhang, Han-Cheng</creatorcontrib><creatorcontrib>White, Kimberley B.</creatorcontrib><creatorcontrib>de Garavilla, Lawrence</creatorcontrib><creatorcontrib>Wang, Yuanping</creatorcontrib><creatorcontrib>Minor, Lisa K.</creatorcontrib><creatorcontrib>Tounge, Brett A.</creatorcontrib><creatorcontrib>Barnakov, Alexander N.</creatorcontrib><creatorcontrib>Lewandowski, Frank</creatorcontrib><creatorcontrib>Milligan, Cynthia</creatorcontrib><creatorcontrib>Spurlino, John C.</creatorcontrib><creatorcontrib>Abraham, William M.</creatorcontrib><creatorcontrib>Boswell-Smith, Victoria</creatorcontrib><creatorcontrib>Page, Clive P.</creatorcontrib><creatorcontrib>Maryanoff, Bruce E.</creatorcontrib><title>Potent, nonpeptide inhibitors of human mast cell tryptase. Synthesis and biological evaluation of novel spirocyclic piperidine amide derivatives</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem Lett</addtitle><description>We have explored a series of spirocyclic piperidine amide derivatives (
5) as tryptase inhibitors. Thus,
4 (JNJ-27390467) was identified as a potent, selective tryptase inhibitor with oral efficacy in two animal models of airway inflammation (sheep and guinea pig asthma models). An X-ray co-crystal structure of
4
·
tryptase revealed a hydrophobic pocket in the enzyme’s active site, which is induced by the phenylethynyl group and is comprised of amino acid residues from two different monomers of the tetrameric protein.</description><subject>Administration, Oral</subject><subject>Animals</subject><subject>Asthma</subject><subject>Asthma - drug therapy</subject><subject>Biological and medical sciences</subject><subject>Biological Availability</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Crystallography, X-Ray</subject><subject>Cytochrome P-450 Enzyme Inhibitors</subject><subject>Disease Models, Animal</subject><subject>Dogs</subject><subject>Guinea Pigs</subject><subject>Humans</subject><subject>Inhibitor</subject><subject>Medical sciences</subject><subject>Microsomes, Liver - drug effects</subject><subject>Microsomes, Liver - enzymology</subject><subject>Molecular Structure</subject><subject>Pharmacology. Drug treatments</subject><subject>Rats</subject><subject>Respiratory Hypersensitivity - drug therapy</subject><subject>Respiratory system</subject><subject>Serine Proteinase Inhibitors - chemical synthesis</subject><subject>Serine Proteinase Inhibitors - pharmacokinetics</subject><subject>Serine Proteinase Inhibitors - pharmacology</subject><subject>Sheep</subject><subject>Spectrometry, Mass, Electrospray Ionization</subject><subject>Spiro Compounds - chemical synthesis</subject><subject>Spiro Compounds - pharmacokinetics</subject><subject>Spiro Compounds - pharmacology</subject><subject>Spiropiperidine</subject><subject>Trypsin - metabolism</subject><subject>Tryptase</subject><subject>Tryptases - antagonists & inhibitors</subject><subject>Tryptases - metabolism</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>eNqFkcuKFDEUhgtRnJ7RF3Ah2ehqujy51QXcyOANBhRUcBdSySk7TVVSJqmCfgsf2Sq60Z2uQuD7_-ScryieUSgp0OrVsexGM5QMoCmBltDyB8WOikrsuQD5sNhBW8G-acX3q-I6pSMAFSDE4-KKNqxmvOK74tfnkNHnW-KDn3DKziJx_uA6l0NMJPTkMI_ak1GnTAwOA8nxNGWdsCRfTj4fMLlEtLekc2EIP5zRA8FFD7POLvitwIcFB5ImF4M5mcEZMrkJo7POI9Hj9qJdr8saWDA9KR71ekj49HLeFN_evf1692F__-n9x7s393sjqMz7qmas5wzQStkLQ2VjqkpILRFakHUnENvaUgnUatkIy422BtoaKsGNscBvipfn3imGnzOmrEaXtgG1xzAnVYMA4JT9F6Qt56Kpt0Z2Bk0MKUXs1RTdqONJUVCbMHVUmzC1CVNA1SpsDT2_tM_diPZv5GJoBV5cAJ3W3fZRe-PSH44BozWT7cq9PnO4Lm1xGFUyDr1B6yKarGxw__rHb8DTtvE</recordid><startdate>20080315</startdate><enddate>20080315</enddate><creator>Costanzo, Michael J.</creator><creator>Yabut, Stephen C.</creator><creator>Zhang, Han-Cheng</creator><creator>White, Kimberley B.</creator><creator>de Garavilla, Lawrence</creator><creator>Wang, Yuanping</creator><creator>Minor, Lisa K.</creator><creator>Tounge, Brett A.</creator><creator>Barnakov, Alexander N.</creator><creator>Lewandowski, Frank</creator><creator>Milligan, Cynthia</creator><creator>Spurlino, John C.</creator><creator>Abraham, William M.</creator><creator>Boswell-Smith, Victoria</creator><creator>Page, Clive P.</creator><creator>Maryanoff, Bruce E.</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><scope>7X8</scope></search><sort><creationdate>20080315</creationdate><title>Potent, nonpeptide inhibitors of human mast cell tryptase. Synthesis and biological evaluation of novel spirocyclic piperidine amide derivatives</title><author>Costanzo, Michael J. ; Yabut, Stephen C. ; Zhang, Han-Cheng ; White, Kimberley B. ; de Garavilla, Lawrence ; Wang, Yuanping ; Minor, Lisa K. ; Tounge, Brett A. ; Barnakov, Alexander N. ; Lewandowski, Frank ; Milligan, Cynthia ; Spurlino, John C. ; Abraham, William M. ; Boswell-Smith, Victoria ; Page, Clive P. ; Maryanoff, Bruce E.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c415t-6722f320ed55f4c158c6645a5e09057b4ee97d1501da584d3cadc0970643ccd03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Administration, Oral</topic><topic>Animals</topic><topic>Asthma</topic><topic>Asthma - drug therapy</topic><topic>Biological and medical sciences</topic><topic>Biological Availability</topic><topic>Chromatography, High Pressure Liquid</topic><topic>Crystallography, X-Ray</topic><topic>Cytochrome P-450 Enzyme Inhibitors</topic><topic>Disease Models, Animal</topic><topic>Dogs</topic><topic>Guinea Pigs</topic><topic>Humans</topic><topic>Inhibitor</topic><topic>Medical sciences</topic><topic>Microsomes, Liver - drug effects</topic><topic>Microsomes, Liver - enzymology</topic><topic>Molecular Structure</topic><topic>Pharmacology. Drug treatments</topic><topic>Rats</topic><topic>Respiratory Hypersensitivity - drug therapy</topic><topic>Respiratory system</topic><topic>Serine Proteinase Inhibitors - chemical synthesis</topic><topic>Serine Proteinase Inhibitors - pharmacokinetics</topic><topic>Serine Proteinase Inhibitors - pharmacology</topic><topic>Sheep</topic><topic>Spectrometry, Mass, Electrospray Ionization</topic><topic>Spiro Compounds - chemical synthesis</topic><topic>Spiro Compounds - pharmacokinetics</topic><topic>Spiro Compounds - pharmacology</topic><topic>Spiropiperidine</topic><topic>Trypsin - metabolism</topic><topic>Tryptase</topic><topic>Tryptases - antagonists & inhibitors</topic><topic>Tryptases - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Costanzo, Michael J.</creatorcontrib><creatorcontrib>Yabut, Stephen C.</creatorcontrib><creatorcontrib>Zhang, Han-Cheng</creatorcontrib><creatorcontrib>White, Kimberley B.</creatorcontrib><creatorcontrib>de Garavilla, Lawrence</creatorcontrib><creatorcontrib>Wang, Yuanping</creatorcontrib><creatorcontrib>Minor, Lisa K.</creatorcontrib><creatorcontrib>Tounge, Brett A.</creatorcontrib><creatorcontrib>Barnakov, Alexander N.</creatorcontrib><creatorcontrib>Lewandowski, Frank</creatorcontrib><creatorcontrib>Milligan, Cynthia</creatorcontrib><creatorcontrib>Spurlino, John C.</creatorcontrib><creatorcontrib>Abraham, William M.</creatorcontrib><creatorcontrib>Boswell-Smith, Victoria</creatorcontrib><creatorcontrib>Page, Clive P.</creatorcontrib><creatorcontrib>Maryanoff, Bruce E.</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><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Costanzo, Michael J.</au><au>Yabut, Stephen C.</au><au>Zhang, Han-Cheng</au><au>White, Kimberley B.</au><au>de Garavilla, Lawrence</au><au>Wang, Yuanping</au><au>Minor, Lisa K.</au><au>Tounge, Brett A.</au><au>Barnakov, Alexander N.</au><au>Lewandowski, Frank</au><au>Milligan, Cynthia</au><au>Spurlino, John C.</au><au>Abraham, William M.</au><au>Boswell-Smith, Victoria</au><au>Page, Clive P.</au><au>Maryanoff, Bruce E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Potent, nonpeptide inhibitors of human mast cell tryptase. Synthesis and biological evaluation of novel spirocyclic piperidine amide derivatives</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2008-03-15</date><risdate>2008</risdate><volume>18</volume><issue>6</issue><spage>2114</spage><epage>2121</epage><pages>2114-2121</pages><issn>0960-894X</issn><issn>0968-0896</issn><eissn>1464-3405</eissn><eissn>1464-3391</eissn><abstract>We have explored a series of spirocyclic piperidine amide derivatives (
5) as tryptase inhibitors. Thus,
4 (JNJ-27390467) was identified as a potent, selective tryptase inhibitor with oral efficacy in two animal models of airway inflammation (sheep and guinea pig asthma models). An X-ray co-crystal structure of
4
·
tryptase revealed a hydrophobic pocket in the enzyme’s active site, which is induced by the phenylethynyl group and is comprised of amino acid residues from two different monomers of the tetrameric protein.</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>18272363</pmid><doi>10.1016/j.bmcl.2008.01.093</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry, 2008-03, Vol.18 (6), p.2114-2121 |
| issn | 0960-894X 0968-0896 1464-3405 1464-3391 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_70400312 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Administration, Oral Animals Asthma Asthma - drug therapy Biological and medical sciences Biological Availability Chromatography, High Pressure Liquid Crystallography, X-Ray Cytochrome P-450 Enzyme Inhibitors Disease Models, Animal Dogs Guinea Pigs Humans Inhibitor Medical sciences Microsomes, Liver - drug effects Microsomes, Liver - enzymology Molecular Structure Pharmacology. Drug treatments Rats Respiratory Hypersensitivity - drug therapy Respiratory system Serine Proteinase Inhibitors - chemical synthesis Serine Proteinase Inhibitors - pharmacokinetics Serine Proteinase Inhibitors - pharmacology Sheep Spectrometry, Mass, Electrospray Ionization Spiro Compounds - chemical synthesis Spiro Compounds - pharmacokinetics Spiro Compounds - pharmacology Spiropiperidine Trypsin - metabolism Tryptase Tryptases - antagonists & inhibitors Tryptases - metabolism |
| title | Potent, nonpeptide inhibitors of human mast cell tryptase. Synthesis and biological evaluation of novel spirocyclic piperidine amide derivatives |
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