Novel Selective PDE4 Inhibitors. 3. In Vivo Antiinflammatory Activity of a New Series of N-Substituted cis-Tetra- and cis-Hexahydrophthalazinones
The synthesis and biological activities of a series of N-substituted cis-4a,5,6,7,8,8a-hexa- and cis-4a,5,8,8a-tetrahydro-2H-phthalazin-1-ones are described. It was found that compounds bearing a cycloalkyl group at the 2-position exhibit the highest PDE4 inhibitory activities (pIC50 = 8.6−9.4). The...
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| Veröffentlicht in: | Journal of medicinal chemistry 2002-06, Vol.45 (12), p.2520-2525 |
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| container_title | Journal of medicinal chemistry |
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| creator | Van der Mey, Margaretha Boss, Hildegard Hatzelmann, Armin Van der Laan, Ivonne J Sterk, Geert J Timmerman, Hendrik |
| description | The synthesis and biological activities of a series of N-substituted cis-4a,5,6,7,8,8a-hexa- and cis-4a,5,8,8a-tetrahydro-2H-phthalazin-1-ones are described. It was found that compounds bearing a cycloalkyl group at the 2-position exhibit the highest PDE4 inhibitory activities (pIC50 = 8.6−9.4). The N-cycloheptyl- and N-adamantanyltetrahydrophthalazinones (7h, 8, 10, 11) show high in vivo antiinflammatory activities after oral application. Additionally, some phthalazinones were found to exhibit potent suppression of LPS-induced TNFα release and show moderate potency against fMLP-stimulated production of ROS. |
| doi_str_mv | 10.1021/jm0110340 |
| format | Article |
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In Vivo Antiinflammatory Activity of a New Series of N-Substituted cis-Tetra- and cis-Hexahydrophthalazinones</title><source>MEDLINE</source><source>ACS Publications</source><creator>Van der Mey, Margaretha ; Boss, Hildegard ; Hatzelmann, Armin ; Van der Laan, Ivonne J ; Sterk, Geert J ; Timmerman, Hendrik</creator><creatorcontrib>Van der Mey, Margaretha ; Boss, Hildegard ; Hatzelmann, Armin ; Van der Laan, Ivonne J ; Sterk, Geert J ; Timmerman, Hendrik</creatorcontrib><description>The synthesis and biological activities of a series of N-substituted cis-4a,5,6,7,8,8a-hexa- and cis-4a,5,8,8a-tetrahydro-2H-phthalazin-1-ones are described. It was found that compounds bearing a cycloalkyl group at the 2-position exhibit the highest PDE4 inhibitory activities (pIC50 = 8.6−9.4). The N-cycloheptyl- and N-adamantanyltetrahydrophthalazinones (7h, 8, 10, 11) show high in vivo antiinflammatory activities after oral application. Additionally, some phthalazinones were found to exhibit potent suppression of LPS-induced TNFα release and show moderate potency against fMLP-stimulated production of ROS.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm0110340</identifier><identifier>PMID: 12036360</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors ; Adamantane - analogs & derivatives ; Adamantane - chemical synthesis ; Adamantane - chemistry ; Adamantane - pharmacology ; Administration, Oral ; Animals ; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis ; Anti-Inflammatory Agents, Non-Steroidal - chemistry ; Anti-Inflammatory Agents, Non-Steroidal - pharmacology ; Biological and medical sciences ; Bones, joints and connective tissue. Antiinflammatory agents ; Cyclic Nucleotide Phosphodiesterases, Type 3 ; Cyclic Nucleotide Phosphodiesterases, Type 4 ; Cycloheptanes - chemical synthesis ; Cycloheptanes - chemistry ; Cycloheptanes - pharmacology ; Edema - drug therapy ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Female ; Humans ; In Vitro Techniques ; Leukocytes, Mononuclear - drug effects ; Leukocytes, Mononuclear - metabolism ; Lipopolysaccharides - pharmacology ; Luminescent Measurements ; Medical sciences ; Mice ; Pharmacology. Drug treatments ; Phthalazines - chemical synthesis ; Phthalazines - chemistry ; Phthalazines - pharmacology ; Reactive Oxygen Species - metabolism ; Structure-Activity Relationship ; Tumor Necrosis Factor-alpha - metabolism</subject><ispartof>Journal of medicinal chemistry, 2002-06, Vol.45 (12), p.2520-2525</ispartof><rights>Copyright © 2002 American Chemical Society</rights><rights>2002 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a404t-add51257e58eb80c69731273f4b6a5a64a1a0c649276395c733d1f93426ac33c3</citedby><cites>FETCH-LOGICAL-a404t-add51257e58eb80c69731273f4b6a5a64a1a0c649276395c733d1f93426ac33c3</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/jm0110340$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm0110340$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>315,782,786,2767,27083,27931,27932,56745,56795</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=13696260$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12036360$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Van der Mey, Margaretha</creatorcontrib><creatorcontrib>Boss, Hildegard</creatorcontrib><creatorcontrib>Hatzelmann, Armin</creatorcontrib><creatorcontrib>Van der Laan, Ivonne J</creatorcontrib><creatorcontrib>Sterk, Geert J</creatorcontrib><creatorcontrib>Timmerman, Hendrik</creatorcontrib><title>Novel Selective PDE4 Inhibitors. 3. In Vivo Antiinflammatory Activity of a New Series of N-Substituted cis-Tetra- and cis-Hexahydrophthalazinones</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The synthesis and biological activities of a series of N-substituted cis-4a,5,6,7,8,8a-hexa- and cis-4a,5,8,8a-tetrahydro-2H-phthalazin-1-ones are described. It was found that compounds bearing a cycloalkyl group at the 2-position exhibit the highest PDE4 inhibitory activities (pIC50 = 8.6−9.4). The N-cycloheptyl- and N-adamantanyltetrahydrophthalazinones (7h, 8, 10, 11) show high in vivo antiinflammatory activities after oral application. Additionally, some phthalazinones were found to exhibit potent suppression of LPS-induced TNFα release and show moderate potency against fMLP-stimulated production of ROS.</description><subject>3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors</subject><subject>Adamantane - analogs & derivatives</subject><subject>Adamantane - chemical synthesis</subject><subject>Adamantane - chemistry</subject><subject>Adamantane - pharmacology</subject><subject>Administration, Oral</subject><subject>Animals</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - chemistry</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Bones, joints and connective tissue. Antiinflammatory agents</subject><subject>Cyclic Nucleotide Phosphodiesterases, Type 3</subject><subject>Cyclic Nucleotide Phosphodiesterases, Type 4</subject><subject>Cycloheptanes - chemical synthesis</subject><subject>Cycloheptanes - chemistry</subject><subject>Cycloheptanes - pharmacology</subject><subject>Edema - drug therapy</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Female</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Leukocytes, Mononuclear - drug effects</subject><subject>Leukocytes, Mononuclear - metabolism</subject><subject>Lipopolysaccharides - pharmacology</subject><subject>Luminescent Measurements</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Pharmacology. Drug treatments</subject><subject>Phthalazines - chemical synthesis</subject><subject>Phthalazines - chemistry</subject><subject>Phthalazines - pharmacology</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Structure-Activity Relationship</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkM1uEzEURi0EoqGw4AWQNyCxmOC_8WSWUVvaSiUUJVTsrDsej-IwM05tT9r0LXhjHBI1G1bW53v86fog9J6SMSWMfll1hFLCBXmBRjRnJBMTIl6iESGMZUwyfoLehLAihHDK-Gt0QhnhkksyQn9mbmNaPDet0dFuDL49vxD4ul_aykbnwxjzcYr4zm4cnvbR2r5poesgDbd4untj4xa7BgOemYdU5K0JuzzL5kMVoo1DNDXWNmQLEz1kGPp9vDKPsNzW3q2XcQktPNne9Sa8Ra8aaIN5dzhP0c-vF4uzq-zm--X12fQmA0FEzKCuc8rywuQTU02IlmWRPlfwRlQScpACKKRbUbJC8jLXBec1bUoumATNuean6NO-d-3d_WBCVJ0N2rQt9MYNQRW0YDLnNIGf96D2LgRvGrX2tgO_VZSonX_17D-xHw6lQ9WZ-kgehCfg4wGAoKFtPPTJxZHjspTsH5ftORuieXyeg_-tZMGLXC1u5-oXP79kd99K9ePYCzqolRt8n9z9Z8G_5oynKA</recordid><startdate>20020606</startdate><enddate>20020606</enddate><creator>Van der Mey, Margaretha</creator><creator>Boss, Hildegard</creator><creator>Hatzelmann, Armin</creator><creator>Van der Laan, Ivonne J</creator><creator>Sterk, Geert J</creator><creator>Timmerman, Hendrik</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>20020606</creationdate><title>Novel Selective PDE4 Inhibitors. 3. In Vivo Antiinflammatory Activity of a New Series of N-Substituted cis-Tetra- and cis-Hexahydrophthalazinones</title><author>Van der Mey, Margaretha ; Boss, Hildegard ; Hatzelmann, Armin ; Van der Laan, Ivonne J ; Sterk, Geert J ; Timmerman, Hendrik</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a404t-add51257e58eb80c69731273f4b6a5a64a1a0c649276395c733d1f93426ac33c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors</topic><topic>Adamantane - analogs & derivatives</topic><topic>Adamantane - chemical synthesis</topic><topic>Adamantane - chemistry</topic><topic>Adamantane - pharmacology</topic><topic>Administration, Oral</topic><topic>Animals</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - chemistry</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Bones, joints and connective tissue. Antiinflammatory agents</topic><topic>Cyclic Nucleotide Phosphodiesterases, Type 3</topic><topic>Cyclic Nucleotide Phosphodiesterases, Type 4</topic><topic>Cycloheptanes - chemical synthesis</topic><topic>Cycloheptanes - chemistry</topic><topic>Cycloheptanes - pharmacology</topic><topic>Edema - drug therapy</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Female</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Leukocytes, Mononuclear - drug effects</topic><topic>Leukocytes, Mononuclear - metabolism</topic><topic>Lipopolysaccharides - pharmacology</topic><topic>Luminescent Measurements</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Pharmacology. Drug treatments</topic><topic>Phthalazines - chemical synthesis</topic><topic>Phthalazines - chemistry</topic><topic>Phthalazines - pharmacology</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Structure-Activity Relationship</topic><topic>Tumor Necrosis Factor-alpha - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Van der Mey, Margaretha</creatorcontrib><creatorcontrib>Boss, Hildegard</creatorcontrib><creatorcontrib>Hatzelmann, Armin</creatorcontrib><creatorcontrib>Van der Laan, Ivonne J</creatorcontrib><creatorcontrib>Sterk, Geert J</creatorcontrib><creatorcontrib>Timmerman, Hendrik</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>Van der Mey, Margaretha</au><au>Boss, Hildegard</au><au>Hatzelmann, Armin</au><au>Van der Laan, Ivonne J</au><au>Sterk, Geert J</au><au>Timmerman, Hendrik</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Novel Selective PDE4 Inhibitors. 3. In Vivo Antiinflammatory Activity of a New Series of N-Substituted cis-Tetra- and cis-Hexahydrophthalazinones</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2002-06-06</date><risdate>2002</risdate><volume>45</volume><issue>12</issue><spage>2520</spage><epage>2525</epage><pages>2520-2525</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>The synthesis and biological activities of a series of N-substituted cis-4a,5,6,7,8,8a-hexa- and cis-4a,5,8,8a-tetrahydro-2H-phthalazin-1-ones are described. It was found that compounds bearing a cycloalkyl group at the 2-position exhibit the highest PDE4 inhibitory activities (pIC50 = 8.6−9.4). The N-cycloheptyl- and N-adamantanyltetrahydrophthalazinones (7h, 8, 10, 11) show high in vivo antiinflammatory activities after oral application. Additionally, some phthalazinones were found to exhibit potent suppression of LPS-induced TNFα release and show moderate potency against fMLP-stimulated production of ROS.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>12036360</pmid><doi>10.1021/jm0110340</doi><tpages>6</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2002-06, Vol.45 (12), p.2520-2525 |
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| subjects | 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors Adamantane - analogs & derivatives Adamantane - chemical synthesis Adamantane - chemistry Adamantane - pharmacology Administration, Oral Animals Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis Anti-Inflammatory Agents, Non-Steroidal - chemistry Anti-Inflammatory Agents, Non-Steroidal - pharmacology Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Cyclic Nucleotide Phosphodiesterases, Type 3 Cyclic Nucleotide Phosphodiesterases, Type 4 Cycloheptanes - chemical synthesis Cycloheptanes - chemistry Cycloheptanes - pharmacology Edema - drug therapy Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Female Humans In Vitro Techniques Leukocytes, Mononuclear - drug effects Leukocytes, Mononuclear - metabolism Lipopolysaccharides - pharmacology Luminescent Measurements Medical sciences Mice Pharmacology. Drug treatments Phthalazines - chemical synthesis Phthalazines - chemistry Phthalazines - pharmacology Reactive Oxygen Species - metabolism Structure-Activity Relationship Tumor Necrosis Factor-alpha - metabolism |
| title | Novel Selective PDE4 Inhibitors. 3. In Vivo Antiinflammatory Activity of a New Series of N-Substituted cis-Tetra- and cis-Hexahydrophthalazinones |
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