Topical nonsteroidal antipsoriatic agents. 1. 1,2,3,4-Tetraoxygenated naphthalene derivatives
On the basis of previous observations that both 2,3-dihydro-2,2,3,3-tetrahydroxy-1,4-naphthoquinone (oxoline, 1) and 6-chloroisonaphthazarin (2) had demonstrated antipsoriatic activity in vivo, a series of structural derivatives of 2 were prepared and examined in the Scholtz-Dumas topical psoriasis...
Gespeichert in:
| Veröffentlicht in: | Journal of medicinal chemistry 1986-08, Vol.29 (8), p.1504-1511 |
|---|---|
| Hauptverfasser: | , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 1511 |
|---|---|
| container_issue | 8 |
| container_start_page | 1504 |
| container_title | Journal of medicinal chemistry |
| container_volume | 29 |
| creator | Jones, Gordon H Venuti, Michael C Young, John M Murthy, D. V. Krishna Loe, Brad E Simpson, Richard A Berks, Andrew H Spires, Doreen A Maloney, Patrick J |
| description | On the basis of previous observations that both 2,3-dihydro-2,2,3,3-tetrahydroxy-1,4-naphthoquinone (oxoline, 1) and 6-chloroisonaphthazarin (2) had demonstrated antipsoriatic activity in vivo, a series of structural derivatives of 2 were prepared and examined in the Scholtz-Dumas topical psoriasis bioassay. Of these six (5, 6, 9a, 10, 11a, 11b), the most effective compound was found to be 6-chloro-1,4-diacetoxy-2,3-dimethoxynaphthalene (RS-43179, lonapalene, 11a). An extensive series of 1,2,3,4-tetraoxygenated naphthalenes (16-74) incorporating variations of the ester, ether, and aryl substituents were prepared as analogues of 11a to examine the structural requirements for activity and were screened in vivo as inhibitors of arachidonic acid induced mouse ear edema, a topical bioassay capable of detecting 5-lipoxygenase inhibitors. Net lipophilicity, hydrolytic stability, and ring substitution play significant roles in determining the observed in vivo activity. Lonapalene (11a) is currently in clinical development as a topically applied nonsteroidal antipsoriatic agent. |
| doi_str_mv | 10.1021/jm00158a031 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_76959590</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>76959590</sourcerecordid><originalsourceid>FETCH-LOGICAL-a286t-bdd8ee9de1662e319edb1cc49bc179623b0974a2af00f2a06abdf2af716c820a3</originalsourceid><addsrcrecordid>eNptkEFP3DAQRi3UCraUU8-VcmoPbOjYSZzkWFFaUFeiFYs4IWtiT8DbbJzaXgT_vka7Qj0gjzSyvufx6DH2gcMJB8G_rNYAvGoQCr7HZrwSkJcNlG_YDECIXEhRHLB3IawAEiKKfbZfAJdCNjN2u3ST1ThkoxtDJO-sSRcco52C8xaj1Rne0RjDScZTzcW8mJf5kqJH9_iUEoxkshGn-3iPA42UGfL2IT18oPCeve1xCHS064fs-vvZ8vQ8X1z-uDj9ushRNDLmnTENUWuISymo4C2Zjmtdtp3mdZvW76CtSxTYA_QCQWJnUu9rLnUjAItD9mk7d_Lu74ZCVGsbNA0DjuQ2QdWyrdKBBB5vQe1dCJ56NXm7Rv-kOKhnmeo_mYn-uBu76dZkXtidvZTn29wmdY8vMfo_StZFXanlryt1Xt0svlWL3-pn4j9vedRBrdzGj0nKqz__A41ci1c</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>76959590</pqid></control><display><type>article</type><title>Topical nonsteroidal antipsoriatic agents. 1. 1,2,3,4-Tetraoxygenated naphthalene derivatives</title><source>MEDLINE</source><source>American Chemical Society Journals</source><creator>Jones, Gordon H ; Venuti, Michael C ; Young, John M ; Murthy, D. V. Krishna ; Loe, Brad E ; Simpson, Richard A ; Berks, Andrew H ; Spires, Doreen A ; Maloney, Patrick J</creator><creatorcontrib>Jones, Gordon H ; Venuti, Michael C ; Young, John M ; Murthy, D. V. Krishna ; Loe, Brad E ; Simpson, Richard A ; Berks, Andrew H ; Spires, Doreen A ; Maloney, Patrick J</creatorcontrib><description>On the basis of previous observations that both 2,3-dihydro-2,2,3,3-tetrahydroxy-1,4-naphthoquinone (oxoline, 1) and 6-chloroisonaphthazarin (2) had demonstrated antipsoriatic activity in vivo, a series of structural derivatives of 2 were prepared and examined in the Scholtz-Dumas topical psoriasis bioassay. Of these six (5, 6, 9a, 10, 11a, 11b), the most effective compound was found to be 6-chloro-1,4-diacetoxy-2,3-dimethoxynaphthalene (RS-43179, lonapalene, 11a). An extensive series of 1,2,3,4-tetraoxygenated naphthalenes (16-74) incorporating variations of the ester, ether, and aryl substituents were prepared as analogues of 11a to examine the structural requirements for activity and were screened in vivo as inhibitors of arachidonic acid induced mouse ear edema, a topical bioassay capable of detecting 5-lipoxygenase inhibitors. Net lipophilicity, hydrolytic stability, and ring substitution play significant roles in determining the observed in vivo activity. Lonapalene (11a) is currently in clinical development as a topically applied nonsteroidal antipsoriatic agent.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00158a031</identifier><identifier>PMID: 3016268</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors ; Administration, Topical ; Animals ; Arachidonate Lipoxygenases ; Arachidonic Acid ; Arachidonic Acids ; Biological Assay ; Edema - chemically induced ; Edema - drug therapy ; Female ; Humans ; Lipoxygenase Inhibitors ; Mice ; Naphthalenes - chemical synthesis ; Naphthalenes - therapeutic use ; Neutrophils - enzymology ; Ornithine Decarboxylase Inhibitors ; Oxygen ; Psoriasis - drug therapy ; Structure-Activity Relationship ; Tetrahydronaphthalenes - chemical synthesis ; Tetrahydronaphthalenes - therapeutic use</subject><ispartof>Journal of medicinal chemistry, 1986-08, Vol.29 (8), p.1504-1511</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a286t-bdd8ee9de1662e319edb1cc49bc179623b0974a2af00f2a06abdf2af716c820a3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm00158a031$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00158a031$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,778,782,2754,27065,27913,27914,56727,56777</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/3016268$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jones, Gordon H</creatorcontrib><creatorcontrib>Venuti, Michael C</creatorcontrib><creatorcontrib>Young, John M</creatorcontrib><creatorcontrib>Murthy, D. V. Krishna</creatorcontrib><creatorcontrib>Loe, Brad E</creatorcontrib><creatorcontrib>Simpson, Richard A</creatorcontrib><creatorcontrib>Berks, Andrew H</creatorcontrib><creatorcontrib>Spires, Doreen A</creatorcontrib><creatorcontrib>Maloney, Patrick J</creatorcontrib><title>Topical nonsteroidal antipsoriatic agents. 1. 1,2,3,4-Tetraoxygenated naphthalene derivatives</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>On the basis of previous observations that both 2,3-dihydro-2,2,3,3-tetrahydroxy-1,4-naphthoquinone (oxoline, 1) and 6-chloroisonaphthazarin (2) had demonstrated antipsoriatic activity in vivo, a series of structural derivatives of 2 were prepared and examined in the Scholtz-Dumas topical psoriasis bioassay. Of these six (5, 6, 9a, 10, 11a, 11b), the most effective compound was found to be 6-chloro-1,4-diacetoxy-2,3-dimethoxynaphthalene (RS-43179, lonapalene, 11a). An extensive series of 1,2,3,4-tetraoxygenated naphthalenes (16-74) incorporating variations of the ester, ether, and aryl substituents were prepared as analogues of 11a to examine the structural requirements for activity and were screened in vivo as inhibitors of arachidonic acid induced mouse ear edema, a topical bioassay capable of detecting 5-lipoxygenase inhibitors. Net lipophilicity, hydrolytic stability, and ring substitution play significant roles in determining the observed in vivo activity. Lonapalene (11a) is currently in clinical development as a topically applied nonsteroidal antipsoriatic agent.</description><subject>3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors</subject><subject>Administration, Topical</subject><subject>Animals</subject><subject>Arachidonate Lipoxygenases</subject><subject>Arachidonic Acid</subject><subject>Arachidonic Acids</subject><subject>Biological Assay</subject><subject>Edema - chemically induced</subject><subject>Edema - drug therapy</subject><subject>Female</subject><subject>Humans</subject><subject>Lipoxygenase Inhibitors</subject><subject>Mice</subject><subject>Naphthalenes - chemical synthesis</subject><subject>Naphthalenes - therapeutic use</subject><subject>Neutrophils - enzymology</subject><subject>Ornithine Decarboxylase Inhibitors</subject><subject>Oxygen</subject><subject>Psoriasis - drug therapy</subject><subject>Structure-Activity Relationship</subject><subject>Tetrahydronaphthalenes - chemical synthesis</subject><subject>Tetrahydronaphthalenes - therapeutic use</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1986</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkEFP3DAQRi3UCraUU8-VcmoPbOjYSZzkWFFaUFeiFYs4IWtiT8DbbJzaXgT_vka7Qj0gjzSyvufx6DH2gcMJB8G_rNYAvGoQCr7HZrwSkJcNlG_YDECIXEhRHLB3IawAEiKKfbZfAJdCNjN2u3ST1ThkoxtDJO-sSRcco52C8xaj1Rne0RjDScZTzcW8mJf5kqJH9_iUEoxkshGn-3iPA42UGfL2IT18oPCeve1xCHS064fs-vvZ8vQ8X1z-uDj9ushRNDLmnTENUWuISymo4C2Zjmtdtp3mdZvW76CtSxTYA_QCQWJnUu9rLnUjAItD9mk7d_Lu74ZCVGsbNA0DjuQ2QdWyrdKBBB5vQe1dCJ56NXm7Rv-kOKhnmeo_mYn-uBu76dZkXtidvZTn29wmdY8vMfo_StZFXanlryt1Xt0svlWL3-pn4j9vedRBrdzGj0nKqz__A41ci1c</recordid><startdate>19860801</startdate><enddate>19860801</enddate><creator>Jones, Gordon H</creator><creator>Venuti, Michael C</creator><creator>Young, John M</creator><creator>Murthy, D. V. Krishna</creator><creator>Loe, Brad E</creator><creator>Simpson, Richard A</creator><creator>Berks, Andrew H</creator><creator>Spires, Doreen A</creator><creator>Maloney, Patrick J</creator><general>American Chemical Society</general><scope>BSCLL</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>19860801</creationdate><title>Topical nonsteroidal antipsoriatic agents. 1. 1,2,3,4-Tetraoxygenated naphthalene derivatives</title><author>Jones, Gordon H ; Venuti, Michael C ; Young, John M ; Murthy, D. V. Krishna ; Loe, Brad E ; Simpson, Richard A ; Berks, Andrew H ; Spires, Doreen A ; Maloney, Patrick J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a286t-bdd8ee9de1662e319edb1cc49bc179623b0974a2af00f2a06abdf2af716c820a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1986</creationdate><topic>3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors</topic><topic>Administration, Topical</topic><topic>Animals</topic><topic>Arachidonate Lipoxygenases</topic><topic>Arachidonic Acid</topic><topic>Arachidonic Acids</topic><topic>Biological Assay</topic><topic>Edema - chemically induced</topic><topic>Edema - drug therapy</topic><topic>Female</topic><topic>Humans</topic><topic>Lipoxygenase Inhibitors</topic><topic>Mice</topic><topic>Naphthalenes - chemical synthesis</topic><topic>Naphthalenes - therapeutic use</topic><topic>Neutrophils - enzymology</topic><topic>Ornithine Decarboxylase Inhibitors</topic><topic>Oxygen</topic><topic>Psoriasis - drug therapy</topic><topic>Structure-Activity Relationship</topic><topic>Tetrahydronaphthalenes - chemical synthesis</topic><topic>Tetrahydronaphthalenes - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jones, Gordon H</creatorcontrib><creatorcontrib>Venuti, Michael C</creatorcontrib><creatorcontrib>Young, John M</creatorcontrib><creatorcontrib>Murthy, D. V. Krishna</creatorcontrib><creatorcontrib>Loe, Brad E</creatorcontrib><creatorcontrib>Simpson, Richard A</creatorcontrib><creatorcontrib>Berks, Andrew H</creatorcontrib><creatorcontrib>Spires, Doreen A</creatorcontrib><creatorcontrib>Maloney, Patrick J</creatorcontrib><collection>Istex</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>Jones, Gordon H</au><au>Venuti, Michael C</au><au>Young, John M</au><au>Murthy, D. V. Krishna</au><au>Loe, Brad E</au><au>Simpson, Richard A</au><au>Berks, Andrew H</au><au>Spires, Doreen A</au><au>Maloney, Patrick J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Topical nonsteroidal antipsoriatic agents. 1. 1,2,3,4-Tetraoxygenated naphthalene derivatives</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1986-08-01</date><risdate>1986</risdate><volume>29</volume><issue>8</issue><spage>1504</spage><epage>1511</epage><pages>1504-1511</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>On the basis of previous observations that both 2,3-dihydro-2,2,3,3-tetrahydroxy-1,4-naphthoquinone (oxoline, 1) and 6-chloroisonaphthazarin (2) had demonstrated antipsoriatic activity in vivo, a series of structural derivatives of 2 were prepared and examined in the Scholtz-Dumas topical psoriasis bioassay. Of these six (5, 6, 9a, 10, 11a, 11b), the most effective compound was found to be 6-chloro-1,4-diacetoxy-2,3-dimethoxynaphthalene (RS-43179, lonapalene, 11a). An extensive series of 1,2,3,4-tetraoxygenated naphthalenes (16-74) incorporating variations of the ester, ether, and aryl substituents were prepared as analogues of 11a to examine the structural requirements for activity and were screened in vivo as inhibitors of arachidonic acid induced mouse ear edema, a topical bioassay capable of detecting 5-lipoxygenase inhibitors. Net lipophilicity, hydrolytic stability, and ring substitution play significant roles in determining the observed in vivo activity. Lonapalene (11a) is currently in clinical development as a topically applied nonsteroidal antipsoriatic agent.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>3016268</pmid><doi>10.1021/jm00158a031</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 1986-08, Vol.29 (8), p.1504-1511 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_76959590 |
| source | MEDLINE; American Chemical Society Journals |
| subjects | 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors Administration, Topical Animals Arachidonate Lipoxygenases Arachidonic Acid Arachidonic Acids Biological Assay Edema - chemically induced Edema - drug therapy Female Humans Lipoxygenase Inhibitors Mice Naphthalenes - chemical synthesis Naphthalenes - therapeutic use Neutrophils - enzymology Ornithine Decarboxylase Inhibitors Oxygen Psoriasis - drug therapy Structure-Activity Relationship Tetrahydronaphthalenes - chemical synthesis Tetrahydronaphthalenes - therapeutic use |
| title | Topical nonsteroidal antipsoriatic agents. 1. 1,2,3,4-Tetraoxygenated naphthalene derivatives |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-15T10%3A00%3A05IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Topical%20nonsteroidal%20antipsoriatic%20agents.%201.%201,2,3,4-Tetraoxygenated%20naphthalene%20derivatives&rft.jtitle=Journal%20of%20medicinal%20chemistry&rft.au=Jones,%20Gordon%20H&rft.date=1986-08-01&rft.volume=29&rft.issue=8&rft.spage=1504&rft.epage=1511&rft.pages=1504-1511&rft.issn=0022-2623&rft.eissn=1520-4804&rft_id=info:doi/10.1021/jm00158a031&rft_dat=%3Cproquest_cross%3E76959590%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=76959590&rft_id=info:pmid/3016268&rfr_iscdi=true |