Dibenzoxepinone Hydroxylamines and Hydroxamic Acids: Dual Inhibitors of Cyclooxygenase and 5-Lipoxygenase with Potent Topical Antiinflammatory Activity
Hydroxylamine and hydroxamic acid derivatives of a known nonsteroidal antiinflammatory dibenzoxepine series display both cyclooxygenase (CO) and 5-lipoxygenase (5-LO) inhibitory properties. Many of these new dual CO/5-LO inhibitors also exhibit potent topical antiinflammatory activity in the arachid...
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| Veröffentlicht in: | Journal of medicinal chemistry 1996-01, Vol.39 (1), p.246-252 |
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| container_title | Journal of medicinal chemistry |
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| creator | Hamer, R. Richard L Tegeler, John J Kurtz, Ellen S Allen, Richard C Bailey, Steven C Elliott, Mary Ellen Hellyer, Luther Helsley, Grover C Przekop, Penelope Freed, Brian S White, John Martin, Lawrence L |
| description | Hydroxylamine and hydroxamic acid derivatives of a known nonsteroidal antiinflammatory dibenzoxepine series display both cyclooxygenase (CO) and 5-lipoxygenase (5-LO) inhibitory properties. Many of these new dual CO/5-LO inhibitors also exhibit potent topical antiinflammatory activity in the arachidonic acid-induced murine ear edema model. On the basis of their promising profile of in vitro and in vivo activities, hydroxamic acids 24h, 3-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)-N-hydroxy-N-methylpropanamide (HP 977), and 25, 3-(6,11-dihydrodibenz[b,e]oxepin-2-yl)-N-hydroxy-N-methylpropanamide (P10294), were selected as developmental candidates for the topical treatment of inflammatory skin disorders. |
| doi_str_mv | 10.1021/jm950563z |
| format | Article |
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Richard L ; Tegeler, John J ; Kurtz, Ellen S ; Allen, Richard C ; Bailey, Steven C ; Elliott, Mary Ellen ; Hellyer, Luther ; Helsley, Grover C ; Przekop, Penelope ; Freed, Brian S ; White, John ; Martin, Lawrence L</creator><creatorcontrib>Hamer, R. Richard L ; Tegeler, John J ; Kurtz, Ellen S ; Allen, Richard C ; Bailey, Steven C ; Elliott, Mary Ellen ; Hellyer, Luther ; Helsley, Grover C ; Przekop, Penelope ; Freed, Brian S ; White, John ; Martin, Lawrence L</creatorcontrib><description>Hydroxylamine and hydroxamic acid derivatives of a known nonsteroidal antiinflammatory dibenzoxepine series display both cyclooxygenase (CO) and 5-lipoxygenase (5-LO) inhibitory properties. Many of these new dual CO/5-LO inhibitors also exhibit potent topical antiinflammatory activity in the arachidonic acid-induced murine ear edema model. On the basis of their promising profile of in vitro and in vivo activities, hydroxamic acids 24h, 3-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)-N-hydroxy-N-methylpropanamide (HP 977), and 25, 3-(6,11-dihydrodibenz[b,e]oxepin-2-yl)-N-hydroxy-N-methylpropanamide (P10294), were selected as developmental candidates for the topical treatment of inflammatory skin disorders.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm950563z</identifier><identifier>PMID: 8568814</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>3T3 Cells ; Animals ; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis ; Anti-Inflammatory Agents, Non-Steroidal - chemistry ; Anti-Inflammatory Agents, Non-Steroidal - pharmacology ; Arachidonate 5-Lipoxygenase - metabolism ; Arachidonic Acid - pharmacology ; Biological and medical sciences ; Bones, joints and connective tissue. Antiinflammatory agents ; Cyclooxygenase Inhibitors - chemical synthesis ; Cyclooxygenase Inhibitors - chemistry ; Cyclooxygenase Inhibitors - pharmacology ; Dibenzoxepins - chemical synthesis ; Dibenzoxepins - chemistry ; Dibenzoxepins - pharmacology ; Dinoprostone - analysis ; Hydroxamic Acids - chemical synthesis ; Hydroxamic Acids - chemistry ; Hydroxamic Acids - pharmacology ; Hydroxyeicosatetraenoic Acids - analysis ; Hydroxylamines - chemical synthesis ; Hydroxylamines - chemistry ; Hydroxylamines - pharmacology ; Lipoxygenase Inhibitors - chemical synthesis ; Lipoxygenase Inhibitors - chemistry ; Lipoxygenase Inhibitors - pharmacology ; Medical sciences ; Mice ; Molecular Structure ; Pharmacology. 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Richard L</creatorcontrib><creatorcontrib>Tegeler, John J</creatorcontrib><creatorcontrib>Kurtz, Ellen S</creatorcontrib><creatorcontrib>Allen, Richard C</creatorcontrib><creatorcontrib>Bailey, Steven C</creatorcontrib><creatorcontrib>Elliott, Mary Ellen</creatorcontrib><creatorcontrib>Hellyer, Luther</creatorcontrib><creatorcontrib>Helsley, Grover C</creatorcontrib><creatorcontrib>Przekop, Penelope</creatorcontrib><creatorcontrib>Freed, Brian S</creatorcontrib><creatorcontrib>White, John</creatorcontrib><creatorcontrib>Martin, Lawrence L</creatorcontrib><title>Dibenzoxepinone Hydroxylamines and Hydroxamic Acids: Dual Inhibitors of Cyclooxygenase and 5-Lipoxygenase with Potent Topical Antiinflammatory Activity</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Hydroxylamine and hydroxamic acid derivatives of a known nonsteroidal antiinflammatory dibenzoxepine series display both cyclooxygenase (CO) and 5-lipoxygenase (5-LO) inhibitory properties. Many of these new dual CO/5-LO inhibitors also exhibit potent topical antiinflammatory activity in the arachidonic acid-induced murine ear edema model. On the basis of their promising profile of in vitro and in vivo activities, hydroxamic acids 24h, 3-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)-N-hydroxy-N-methylpropanamide (HP 977), and 25, 3-(6,11-dihydrodibenz[b,e]oxepin-2-yl)-N-hydroxy-N-methylpropanamide (P10294), were selected as developmental candidates for the topical treatment of inflammatory skin disorders.</description><subject>3T3 Cells</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>Arachidonate 5-Lipoxygenase - metabolism</subject><subject>Arachidonic Acid - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Bones, joints and connective tissue. Antiinflammatory agents</subject><subject>Cyclooxygenase Inhibitors - chemical synthesis</subject><subject>Cyclooxygenase Inhibitors - chemistry</subject><subject>Cyclooxygenase Inhibitors - pharmacology</subject><subject>Dibenzoxepins - chemical synthesis</subject><subject>Dibenzoxepins - chemistry</subject><subject>Dibenzoxepins - pharmacology</subject><subject>Dinoprostone - analysis</subject><subject>Hydroxamic Acids - chemical synthesis</subject><subject>Hydroxamic Acids - chemistry</subject><subject>Hydroxamic Acids - pharmacology</subject><subject>Hydroxyeicosatetraenoic Acids - analysis</subject><subject>Hydroxylamines - chemical synthesis</subject><subject>Hydroxylamines - chemistry</subject><subject>Hydroxylamines - pharmacology</subject><subject>Lipoxygenase Inhibitors - chemical synthesis</subject><subject>Lipoxygenase Inhibitors - chemistry</subject><subject>Lipoxygenase Inhibitors - pharmacology</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Molecular Structure</subject><subject>Pharmacology. Drug treatments</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1996</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkc1u1DAUhS1EVYaWBQ-AlAUgsQj1T-wk3Y2mlGk1hUod1pbjONRDYgfbaSddseUVeLw-CYaJhg0rS-d891zrXABeIvgeQYxONl1JIWXk4QmYIYphmhUwewpmEGKcYobJM_Dc-w2EkCBMDsFhQVlRoGwGfp3pSpkHu1W9NtaoZDnWzm7HVnTaKJ8IU09SFGQyl7r2p48_fiZng2iTC3OrKx2s84ltksUoWxtnvyojvPo7StOV7v9J9zrcJtc2KBOSte21jBlzE7Q2TVzYiZg0xh1B3-kwHoODRrRevZjeI_Dl_MN6sUxXnz9eLOarVJC8DGlGKBKsErAkkAmEKM1gwbK8aoggFcxKJVmdVQ1jqsoxlrSSGBJSkLrBqCxzcgTe7nJ7Z78PygfeaS9V2wqj7OB5npcFLiGN4LsdKJ313qmG9053wo0cQf7nDnx_h8i-mkKHqlP1npyKj_7ryRc-ttA4YaT2ewyXjKIMRSzdYdoHtd3bwn3jLCc55evrG355tfx0Q68u-Xnk3-x4IT3f2MGZ2Nx_vvcbfhGusw</recordid><startdate>19960105</startdate><enddate>19960105</enddate><creator>Hamer, R. Richard L</creator><creator>Tegeler, John J</creator><creator>Kurtz, Ellen S</creator><creator>Allen, Richard C</creator><creator>Bailey, Steven C</creator><creator>Elliott, Mary Ellen</creator><creator>Hellyer, Luther</creator><creator>Helsley, Grover C</creator><creator>Przekop, Penelope</creator><creator>Freed, Brian S</creator><creator>White, John</creator><creator>Martin, Lawrence L</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>19960105</creationdate><title>Dibenzoxepinone Hydroxylamines and Hydroxamic Acids: Dual Inhibitors of Cyclooxygenase and 5-Lipoxygenase with Potent Topical Antiinflammatory Activity</title><author>Hamer, R. Richard L ; Tegeler, John J ; Kurtz, Ellen S ; Allen, Richard C ; Bailey, Steven C ; Elliott, Mary Ellen ; Hellyer, Luther ; Helsley, Grover C ; Przekop, Penelope ; Freed, Brian S ; White, John ; Martin, Lawrence L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a379t-4351a6ba09306a1155408647bf3a3b049ec6d4bf66eb722c5bc203383df219973</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1996</creationdate><topic>3T3 Cells</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>Arachidonate 5-Lipoxygenase - metabolism</topic><topic>Arachidonic Acid - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Bones, joints and connective tissue. Antiinflammatory agents</topic><topic>Cyclooxygenase Inhibitors - chemical synthesis</topic><topic>Cyclooxygenase Inhibitors - chemistry</topic><topic>Cyclooxygenase Inhibitors - pharmacology</topic><topic>Dibenzoxepins - chemical synthesis</topic><topic>Dibenzoxepins - chemistry</topic><topic>Dibenzoxepins - pharmacology</topic><topic>Dinoprostone - analysis</topic><topic>Hydroxamic Acids - chemical synthesis</topic><topic>Hydroxamic Acids - chemistry</topic><topic>Hydroxamic Acids - pharmacology</topic><topic>Hydroxyeicosatetraenoic Acids - analysis</topic><topic>Hydroxylamines - chemical synthesis</topic><topic>Hydroxylamines - chemistry</topic><topic>Hydroxylamines - pharmacology</topic><topic>Lipoxygenase Inhibitors - chemical synthesis</topic><topic>Lipoxygenase Inhibitors - chemistry</topic><topic>Lipoxygenase Inhibitors - pharmacology</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Molecular Structure</topic><topic>Pharmacology. 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Richard L</creatorcontrib><creatorcontrib>Tegeler, John J</creatorcontrib><creatorcontrib>Kurtz, Ellen S</creatorcontrib><creatorcontrib>Allen, Richard C</creatorcontrib><creatorcontrib>Bailey, Steven C</creatorcontrib><creatorcontrib>Elliott, Mary Ellen</creatorcontrib><creatorcontrib>Hellyer, Luther</creatorcontrib><creatorcontrib>Helsley, Grover C</creatorcontrib><creatorcontrib>Przekop, Penelope</creatorcontrib><creatorcontrib>Freed, Brian S</creatorcontrib><creatorcontrib>White, John</creatorcontrib><creatorcontrib>Martin, Lawrence L</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>Hamer, R. Richard L</au><au>Tegeler, John J</au><au>Kurtz, Ellen S</au><au>Allen, Richard C</au><au>Bailey, Steven C</au><au>Elliott, Mary Ellen</au><au>Hellyer, Luther</au><au>Helsley, Grover C</au><au>Przekop, Penelope</au><au>Freed, Brian S</au><au>White, John</au><au>Martin, Lawrence L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Dibenzoxepinone Hydroxylamines and Hydroxamic Acids: Dual Inhibitors of Cyclooxygenase and 5-Lipoxygenase with Potent Topical Antiinflammatory Activity</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1996-01-05</date><risdate>1996</risdate><volume>39</volume><issue>1</issue><spage>246</spage><epage>252</epage><pages>246-252</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Hydroxylamine and hydroxamic acid derivatives of a known nonsteroidal antiinflammatory dibenzoxepine series display both cyclooxygenase (CO) and 5-lipoxygenase (5-LO) inhibitory properties. Many of these new dual CO/5-LO inhibitors also exhibit potent topical antiinflammatory activity in the arachidonic acid-induced murine ear edema model. On the basis of their promising profile of in vitro and in vivo activities, hydroxamic acids 24h, 3-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)-N-hydroxy-N-methylpropanamide (HP 977), and 25, 3-(6,11-dihydrodibenz[b,e]oxepin-2-yl)-N-hydroxy-N-methylpropanamide (P10294), were selected as developmental candidates for the topical treatment of inflammatory skin disorders.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>8568814</pmid><doi>10.1021/jm950563z</doi><tpages>7</tpages></addata></record> |
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| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 1996-01, Vol.39 (1), p.246-252 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | MEDLINE; American Chemical Society Journals |
| subjects | 3T3 Cells Animals Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis Anti-Inflammatory Agents, Non-Steroidal - chemistry Anti-Inflammatory Agents, Non-Steroidal - pharmacology Arachidonate 5-Lipoxygenase - metabolism Arachidonic Acid - pharmacology Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Cyclooxygenase Inhibitors - chemical synthesis Cyclooxygenase Inhibitors - chemistry Cyclooxygenase Inhibitors - pharmacology Dibenzoxepins - chemical synthesis Dibenzoxepins - chemistry Dibenzoxepins - pharmacology Dinoprostone - analysis Hydroxamic Acids - chemical synthesis Hydroxamic Acids - chemistry Hydroxamic Acids - pharmacology Hydroxyeicosatetraenoic Acids - analysis Hydroxylamines - chemical synthesis Hydroxylamines - chemistry Hydroxylamines - pharmacology Lipoxygenase Inhibitors - chemical synthesis Lipoxygenase Inhibitors - chemistry Lipoxygenase Inhibitors - pharmacology Medical sciences Mice Molecular Structure Pharmacology. Drug treatments Structure-Activity Relationship |
| title | Dibenzoxepinone Hydroxylamines and Hydroxamic Acids: Dual Inhibitors of Cyclooxygenase and 5-Lipoxygenase with Potent Topical Antiinflammatory Activity |
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