2-(Isopropylamino)thieno[3,2-d]pyrimidin-4(3H)-one derivatives as selective phosphodiesterase 7 inhibitors with potent in vivo efficacy
A new series of thienopyrimidinones is synthesized and evaluated as selective phosphodiesterase 7 (PDE7) inhibitors for the treatment of inflammatory diseases. The modification of the substituents on thienopyrimidinone revealed that an isopropylamino group at the 2-position was favorable for aqueous...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2015-05, Vol.25 (9), p.1910-1914 |
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| container_end_page | 1914 |
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| container_issue | 9 |
| container_start_page | 1910 |
| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 25 |
| creator | Endo, Yusuke Kawai, Kentaro Asano, Takeshi Amano, Seiji Asanuma, Yoshihito Sawada, Keisuke Onodera, Yuuta Ueo, Noriko Takahashi, Nobuaki Sonoda, Yo Kamei, Noriyuki Irie, Tetsumi |
| description | A new series of thienopyrimidinones is synthesized and evaluated as selective phosphodiesterase 7 (PDE7) inhibitors for the treatment of inflammatory diseases. The modification of the substituents on thienopyrimidinone revealed that an isopropylamino group at the 2-position was favorable for aqueous solubility. The introduction of 3-pyrrolidines at the 7-position resulted in good solubility, highly potent activity, and good PDE7 selectivity. Among the synthesized compounds, compound 46 exhibited the greatest inhibition of ear edema in a phorbol ester-induced mouse model. |
| doi_str_mv | 10.1016/j.bmcl.2015.03.031 |
| format | Article |
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The modification of the substituents on thienopyrimidinone revealed that an isopropylamino group at the 2-position was favorable for aqueous solubility. The introduction of 3-pyrrolidines at the 7-position resulted in good solubility, highly potent activity, and good PDE7 selectivity. Among the synthesized compounds, compound 46 exhibited the greatest inhibition of ear edema in a phorbol ester-induced mouse model.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2015.03.031</identifier><identifier>PMID: 25866242</identifier><language>eng</language><publisher>England</publisher><subject>Animals ; Cyclic Nucleotide Phosphodiesterases, Type 7 - antagonists & inhibitors ; Cyclic Nucleotide Phosphodiesterases, Type 7 - metabolism ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Edema - chemically induced ; Edema - drug therapy ; Male ; Mice ; Mice, Inbred ICR ; Models, Molecular ; Molecular Structure ; Phorbol Esters ; Pyrimidinones - chemical synthesis ; Pyrimidinones - chemistry ; Pyrimidinones - pharmacology ; Solubility ; Structure-Activity Relationship ; Substrate Specificity</subject><ispartof>Bioorganic & medicinal chemistry letters, 2015-05, Vol.25 (9), p.1910-1914</ispartof><rights>Copyright © 2015 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c373t-981b33465273fc53cfcf42b4e8cf5b9b8121caf83af045750f6c7d00aa67dafa3</citedby><cites>FETCH-LOGICAL-c373t-981b33465273fc53cfcf42b4e8cf5b9b8121caf83af045750f6c7d00aa67dafa3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25866242$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Endo, Yusuke</creatorcontrib><creatorcontrib>Kawai, Kentaro</creatorcontrib><creatorcontrib>Asano, Takeshi</creatorcontrib><creatorcontrib>Amano, Seiji</creatorcontrib><creatorcontrib>Asanuma, Yoshihito</creatorcontrib><creatorcontrib>Sawada, Keisuke</creatorcontrib><creatorcontrib>Onodera, Yuuta</creatorcontrib><creatorcontrib>Ueo, Noriko</creatorcontrib><creatorcontrib>Takahashi, Nobuaki</creatorcontrib><creatorcontrib>Sonoda, Yo</creatorcontrib><creatorcontrib>Kamei, Noriyuki</creatorcontrib><creatorcontrib>Irie, Tetsumi</creatorcontrib><title>2-(Isopropylamino)thieno[3,2-d]pyrimidin-4(3H)-one derivatives as selective phosphodiesterase 7 inhibitors with potent in vivo efficacy</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>A new series of thienopyrimidinones is synthesized and evaluated as selective phosphodiesterase 7 (PDE7) inhibitors for the treatment of inflammatory diseases. The modification of the substituents on thienopyrimidinone revealed that an isopropylamino group at the 2-position was favorable for aqueous solubility. The introduction of 3-pyrrolidines at the 7-position resulted in good solubility, highly potent activity, and good PDE7 selectivity. Among the synthesized compounds, compound 46 exhibited the greatest inhibition of ear edema in a phorbol ester-induced mouse model.</description><subject>Animals</subject><subject>Cyclic Nucleotide Phosphodiesterases, Type 7 - antagonists & inhibitors</subject><subject>Cyclic Nucleotide Phosphodiesterases, Type 7 - metabolism</subject><subject>Disease Models, Animal</subject><subject>Dose-Response Relationship, Drug</subject><subject>Edema - chemically induced</subject><subject>Edema - drug therapy</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred ICR</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Phorbol Esters</subject><subject>Pyrimidinones - chemical synthesis</subject><subject>Pyrimidinones - chemistry</subject><subject>Pyrimidinones - pharmacology</subject><subject>Solubility</subject><subject>Structure-Activity Relationship</subject><subject>Substrate Specificity</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9UdtqGzEQFaUhdi4_0IeiRxsqV3etH4tpm0CgLwkUShBa7QjL7K62q7WDvyC_XZk4hRmGGc4cZs5B6BOjK0aZ_rpb1Z1vV5wytaKiBPuA5kxqSYSk6iOa07WmpFrL3zN0lfOOUiaplJdoxlWlNZd8jl45WdznNIxpOLaui31aTtsIffojvnDSPA_HMXaxiT2RC3G3JKkH3MAYD26KB8jYZZyhBX_q8LBNuWQTIU8wugzY4NhvYx2nNGb8EqctHtIE_VTG-BAPCUMI0Tt_vEEXwbUZbs_1Gj39-P64uSMPv37eb749EC-MmMi6YrUQUituRPBK-OCD5LWEygdVr-uKceZdqIQLVCqjaNDeNJQ6p03jghPXaPHGWz7-uy932i5mD23rekj7bJk2qjKSSVOg_A3qx5TzCMEORQs3Hi2j9mSA3dmTAfZkgKWiBCtLn8_8-7qD5v_Ku-LiH2qPhPM</recordid><startdate>20150501</startdate><enddate>20150501</enddate><creator>Endo, Yusuke</creator><creator>Kawai, Kentaro</creator><creator>Asano, Takeshi</creator><creator>Amano, Seiji</creator><creator>Asanuma, Yoshihito</creator><creator>Sawada, Keisuke</creator><creator>Onodera, Yuuta</creator><creator>Ueo, Noriko</creator><creator>Takahashi, Nobuaki</creator><creator>Sonoda, Yo</creator><creator>Kamei, Noriyuki</creator><creator>Irie, Tetsumi</creator><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>20150501</creationdate><title>2-(Isopropylamino)thieno[3,2-d]pyrimidin-4(3H)-one derivatives as selective phosphodiesterase 7 inhibitors with potent in vivo efficacy</title><author>Endo, Yusuke ; Kawai, Kentaro ; Asano, Takeshi ; Amano, Seiji ; Asanuma, Yoshihito ; Sawada, Keisuke ; Onodera, Yuuta ; Ueo, Noriko ; Takahashi, Nobuaki ; Sonoda, Yo ; Kamei, Noriyuki ; Irie, Tetsumi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c373t-981b33465273fc53cfcf42b4e8cf5b9b8121caf83af045750f6c7d00aa67dafa3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animals</topic><topic>Cyclic Nucleotide Phosphodiesterases, Type 7 - antagonists & inhibitors</topic><topic>Cyclic Nucleotide Phosphodiesterases, Type 7 - metabolism</topic><topic>Disease Models, Animal</topic><topic>Dose-Response Relationship, Drug</topic><topic>Edema - chemically induced</topic><topic>Edema - drug therapy</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred ICR</topic><topic>Models, Molecular</topic><topic>Molecular Structure</topic><topic>Phorbol Esters</topic><topic>Pyrimidinones - chemical synthesis</topic><topic>Pyrimidinones - chemistry</topic><topic>Pyrimidinones - pharmacology</topic><topic>Solubility</topic><topic>Structure-Activity Relationship</topic><topic>Substrate Specificity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Endo, Yusuke</creatorcontrib><creatorcontrib>Kawai, Kentaro</creatorcontrib><creatorcontrib>Asano, Takeshi</creatorcontrib><creatorcontrib>Amano, Seiji</creatorcontrib><creatorcontrib>Asanuma, Yoshihito</creatorcontrib><creatorcontrib>Sawada, Keisuke</creatorcontrib><creatorcontrib>Onodera, Yuuta</creatorcontrib><creatorcontrib>Ueo, Noriko</creatorcontrib><creatorcontrib>Takahashi, Nobuaki</creatorcontrib><creatorcontrib>Sonoda, Yo</creatorcontrib><creatorcontrib>Kamei, Noriyuki</creatorcontrib><creatorcontrib>Irie, Tetsumi</creatorcontrib><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>Endo, Yusuke</au><au>Kawai, Kentaro</au><au>Asano, Takeshi</au><au>Amano, Seiji</au><au>Asanuma, Yoshihito</au><au>Sawada, Keisuke</au><au>Onodera, Yuuta</au><au>Ueo, Noriko</au><au>Takahashi, Nobuaki</au><au>Sonoda, Yo</au><au>Kamei, Noriyuki</au><au>Irie, Tetsumi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>2-(Isopropylamino)thieno[3,2-d]pyrimidin-4(3H)-one derivatives as selective phosphodiesterase 7 inhibitors with potent in vivo efficacy</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2015-05-01</date><risdate>2015</risdate><volume>25</volume><issue>9</issue><spage>1910</spage><epage>1914</epage><pages>1910-1914</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>A new series of thienopyrimidinones is synthesized and evaluated as selective phosphodiesterase 7 (PDE7) inhibitors for the treatment of inflammatory diseases. The modification of the substituents on thienopyrimidinone revealed that an isopropylamino group at the 2-position was favorable for aqueous solubility. The introduction of 3-pyrrolidines at the 7-position resulted in good solubility, highly potent activity, and good PDE7 selectivity. Among the synthesized compounds, compound 46 exhibited the greatest inhibition of ear edema in a phorbol ester-induced mouse model.</abstract><cop>England</cop><pmid>25866242</pmid><doi>10.1016/j.bmcl.2015.03.031</doi><tpages>5</tpages></addata></record> |
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| subjects | Animals Cyclic Nucleotide Phosphodiesterases, Type 7 - antagonists & inhibitors Cyclic Nucleotide Phosphodiesterases, Type 7 - metabolism Disease Models, Animal Dose-Response Relationship, Drug Edema - chemically induced Edema - drug therapy Male Mice Mice, Inbred ICR Models, Molecular Molecular Structure Phorbol Esters Pyrimidinones - chemical synthesis Pyrimidinones - chemistry Pyrimidinones - pharmacology Solubility Structure-Activity Relationship Substrate Specificity |
| title | 2-(Isopropylamino)thieno[3,2-d]pyrimidin-4(3H)-one derivatives as selective phosphodiesterase 7 inhibitors with potent in vivo efficacy |
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