Design and synthesis of potent, orally bioavailable dihydroquinazolinone inhibitors of p38 MAP kinase
The development of potent, orally bioavailable (in rat) and selective dihydroquinazolinone inhibitors of p38α MAP kinase is described. These analogues are hybrids of a pyridinylimidazole p38α inhibitor reported by Merck Research Laboratories and VX-745. Optimization of the C-5 phenyl and the C-7 pip...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2003-01, Vol.13 (2), p.277-280 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Stelmach, John E. Liu, Luping Patel, Sangita B. Pivnichny, James V. Scapin, Giovanna Singh, Suresh Hop, Cornelis E.C.A. Wang, Zhen Strauss, John R. Cameron, Patricia M. Nichols, Elizabeth A. O'Keefe, Stephen J. O'Neill, Edward A. Schmatz, Dennis M. Schwartz, Cheryl D. Thompson, Chris M. Zaller, Dennis M. Doherty, James B. |
| description | The development of potent, orally bioavailable (in rat) and selective dihydroquinazolinone inhibitors of p38α MAP kinase is described. These analogues are hybrids of a pyridinylimidazole p38α inhibitor reported by Merck Research Laboratories and VX-745. Optimization of the C-5 phenyl and the C-7 piperidinyl substituents led to the identification of
15i which gave excellent suppression of TNF-α production in LPS-stimulated whole blood (IC
50=10
nM) and good oral exposure in rats (F=68%, AUCn PO=0.58
μM h).
Graphic |
| doi_str_mv | 10.1016/S0960-894X(02)00752-7 |
| format | Article |
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15i which gave excellent suppression of TNF-α production in LPS-stimulated whole blood (IC
50=10
nM) and good oral exposure in rats (F=68%, AUCn PO=0.58
μM h).
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15i which gave excellent suppression of TNF-α production in LPS-stimulated whole blood (IC
50=10
nM) and good oral exposure in rats (F=68%, AUCn PO=0.58
μM h).
Graphic</description><subject>Animals</subject><subject>Area Under Curve</subject><subject>Biological and medical sciences</subject><subject>Biological Availability</subject><subject>Drug Design</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - pharmacokinetics</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>In Vitro Techniques</subject><subject>Medical sciences</subject><subject>Microsomes, Liver - drug effects</subject><subject>Microsomes, Liver - metabolism</subject><subject>Miscellaneous</subject><subject>Mitogen-Activated Protein Kinases - antagonists & inhibitors</subject><subject>Models, Molecular</subject><subject>Molecular Conformation</subject><subject>Monocytes - drug effects</subject><subject>Monocytes - metabolism</subject><subject>p38 Mitogen-Activated Protein Kinases</subject><subject>Pharmacology. Drug treatments</subject><subject>Quinazolines - chemical synthesis</subject><subject>Quinazolines - pharmacology</subject><subject>Rats</subject><subject>Structure-Activity Relationship</subject><subject>Tumor Necrosis Factor-alpha - antagonists & inhibitors</subject><subject>Tumor Necrosis Factor-alpha - biosynthesis</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkF1rFDEUhoNU7Hb1J7TkpmLB0ZOP-ciVlLZ-QEXBXngXMskZN5pN1mS2sP56Z7qLvfTqcOB5z3l5CDll8IYBa95-A9VA1Sn5_RXwC4C25lX7hCyYbGQlJNRHZPEPOSYnpfwEYBKkfEaOGZcdl0ItCF5j8T8iNdHRsovjaloLTQPdpBHj-JqmbELY0d4nc298MH1A6vxq53L6vfXR_EnBxxSR-rjyvR9T3sdFRz9ffqW_JqTgc_J0MKHgi8Nckrv3N3dXH6vbLx8-XV3eVrZmbKxa1Uk5WIud6hwHU4upsmKN5QKFkA5ZA5ZZaJRoW6jBDWKAVvaONc5aJpbk5f7sZi6HZdRrXyyGYCKmbdEt7zrF5AzWe9DmVErGQW-yX5u80wz0rFc_6NWzOw1cP-jV7ZQ7OzzY9mt0j6mDzwk4PwCmWBOGbKL15ZGTkqu5_pK823M42bj3mHWxHqNF5zPaUbvk_1PlLxE5l5A</recordid><startdate>200301</startdate><enddate>200301</enddate><creator>Stelmach, John E.</creator><creator>Liu, Luping</creator><creator>Patel, Sangita B.</creator><creator>Pivnichny, James V.</creator><creator>Scapin, Giovanna</creator><creator>Singh, Suresh</creator><creator>Hop, Cornelis E.C.A.</creator><creator>Wang, Zhen</creator><creator>Strauss, John R.</creator><creator>Cameron, Patricia M.</creator><creator>Nichols, Elizabeth A.</creator><creator>O'Keefe, Stephen J.</creator><creator>O'Neill, Edward A.</creator><creator>Schmatz, Dennis M.</creator><creator>Schwartz, Cheryl D.</creator><creator>Thompson, Chris M.</creator><creator>Zaller, Dennis M.</creator><creator>Doherty, James B.</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>7X8</scope></search><sort><creationdate>200301</creationdate><title>Design and synthesis of potent, orally bioavailable dihydroquinazolinone inhibitors of p38 MAP kinase</title><author>Stelmach, John E. ; Liu, Luping ; Patel, Sangita B. ; Pivnichny, James V. ; Scapin, Giovanna ; Singh, Suresh ; Hop, Cornelis E.C.A. ; Wang, Zhen ; Strauss, John R. ; Cameron, Patricia M. ; Nichols, Elizabeth A. ; O'Keefe, Stephen J. ; O'Neill, Edward A. ; Schmatz, Dennis M. ; Schwartz, Cheryl D. ; Thompson, Chris M. ; Zaller, Dennis M. ; Doherty, James B.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c511t-79844fcce898d20a53001916c23e334de160c1c069377050df3f074bd16dcc13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Animals</topic><topic>Area Under Curve</topic><topic>Biological and medical sciences</topic><topic>Biological Availability</topic><topic>Drug Design</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - pharmacokinetics</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>In Vitro Techniques</topic><topic>Medical sciences</topic><topic>Microsomes, Liver - drug effects</topic><topic>Microsomes, Liver - metabolism</topic><topic>Miscellaneous</topic><topic>Mitogen-Activated Protein Kinases - antagonists & inhibitors</topic><topic>Models, Molecular</topic><topic>Molecular Conformation</topic><topic>Monocytes - drug effects</topic><topic>Monocytes - metabolism</topic><topic>p38 Mitogen-Activated Protein Kinases</topic><topic>Pharmacology. Drug treatments</topic><topic>Quinazolines - chemical synthesis</topic><topic>Quinazolines - pharmacology</topic><topic>Rats</topic><topic>Structure-Activity Relationship</topic><topic>Tumor Necrosis Factor-alpha - antagonists & inhibitors</topic><topic>Tumor Necrosis Factor-alpha - biosynthesis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Stelmach, John E.</creatorcontrib><creatorcontrib>Liu, Luping</creatorcontrib><creatorcontrib>Patel, Sangita B.</creatorcontrib><creatorcontrib>Pivnichny, James V.</creatorcontrib><creatorcontrib>Scapin, Giovanna</creatorcontrib><creatorcontrib>Singh, Suresh</creatorcontrib><creatorcontrib>Hop, Cornelis E.C.A.</creatorcontrib><creatorcontrib>Wang, Zhen</creatorcontrib><creatorcontrib>Strauss, John R.</creatorcontrib><creatorcontrib>Cameron, Patricia M.</creatorcontrib><creatorcontrib>Nichols, Elizabeth A.</creatorcontrib><creatorcontrib>O'Keefe, Stephen J.</creatorcontrib><creatorcontrib>O'Neill, Edward A.</creatorcontrib><creatorcontrib>Schmatz, Dennis M.</creatorcontrib><creatorcontrib>Schwartz, Cheryl D.</creatorcontrib><creatorcontrib>Thompson, Chris M.</creatorcontrib><creatorcontrib>Zaller, Dennis M.</creatorcontrib><creatorcontrib>Doherty, James B.</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>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Stelmach, John E.</au><au>Liu, Luping</au><au>Patel, Sangita B.</au><au>Pivnichny, James V.</au><au>Scapin, Giovanna</au><au>Singh, Suresh</au><au>Hop, Cornelis E.C.A.</au><au>Wang, Zhen</au><au>Strauss, John R.</au><au>Cameron, Patricia M.</au><au>Nichols, Elizabeth A.</au><au>O'Keefe, Stephen J.</au><au>O'Neill, Edward A.</au><au>Schmatz, Dennis M.</au><au>Schwartz, Cheryl D.</au><au>Thompson, Chris M.</au><au>Zaller, Dennis M.</au><au>Doherty, James B.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design and synthesis of potent, orally bioavailable dihydroquinazolinone inhibitors of p38 MAP kinase</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2003-01</date><risdate>2003</risdate><volume>13</volume><issue>2</issue><spage>277</spage><epage>280</epage><pages>277-280</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>The development of potent, orally bioavailable (in rat) and selective dihydroquinazolinone inhibitors of p38α MAP kinase is described. These analogues are hybrids of a pyridinylimidazole p38α inhibitor reported by Merck Research Laboratories and VX-745. Optimization of the C-5 phenyl and the C-7 piperidinyl substituents led to the identification of
15i which gave excellent suppression of TNF-α production in LPS-stimulated whole blood (IC
50=10
nM) and good oral exposure in rats (F=68%, AUCn PO=0.58
μM h).
Graphic</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>12482439</pmid><doi>10.1016/S0960-894X(02)00752-7</doi><tpages>4</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Bioorganic & medicinal chemistry letters, 2003-01, Vol.13 (2), p.277-280 |
| issn | 0960-894X 1464-3405 |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Animals Area Under Curve Biological and medical sciences Biological Availability Drug Design Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - pharmacokinetics Enzyme Inhibitors - pharmacology In Vitro Techniques Medical sciences Microsomes, Liver - drug effects Microsomes, Liver - metabolism Miscellaneous Mitogen-Activated Protein Kinases - antagonists & inhibitors Models, Molecular Molecular Conformation Monocytes - drug effects Monocytes - metabolism p38 Mitogen-Activated Protein Kinases Pharmacology. Drug treatments Quinazolines - chemical synthesis Quinazolines - pharmacology Rats Structure-Activity Relationship Tumor Necrosis Factor-alpha - antagonists & inhibitors Tumor Necrosis Factor-alpha - biosynthesis |
| title | Design and synthesis of potent, orally bioavailable dihydroquinazolinone inhibitors of p38 MAP kinase |
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