The discovery and synthesis of highly potent subtype selective phosphodiesterase 4D inhibitors
The SAR study of a series of 6-aryloxymethyl-8-aryl substituted quinolines is described. Optimization of the series led to the discovery of compound 26b, a highly potent (IC 50 = 0.6 nM) and selective PDE4D inhibitor with a 75-fold selectivity over the A, B, and C subtypes and over 18,000-fold selec...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2010-09, Vol.20 (18), p.5502-5505 |
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| container_issue | 18 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Aspiotis, Renee Deschênes, Denis Dubé, Daniel Girard, Yves Huang, Zheng Laliberté, France Liu, Susana Papp, Robert Nicholson, Donald W. Young, Robert N. |
| description | The SAR study of a series of 6-aryloxymethyl-8-aryl substituted quinolines is described. Optimization of the series led to the discovery of compound
26b, a highly potent (IC
50
=
0.6
nM) and selective PDE4D inhibitor with a 75-fold selectivity over the A, B, and C subtypes and over 18,000-fold selectivity against other PDE family members. Rat pharmacokinetics and tissue distribution are also summarized. |
| doi_str_mv | 10.1016/j.bmcl.2010.07.076 |
| format | Article |
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26b, a highly potent (IC
50
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0.6
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Drug treatments</subject><subject>Phosphodiesterase 4D inhibitors</subject><subject>Phosphodiesterase Inhibitors - chemical synthesis</subject><subject>Phosphodiesterase Inhibitors - chemistry</subject><subject>Phosphodiesterase Inhibitors - pharmacokinetics</subject><subject>Phosphodiesterase Inhibitors - pharmacology</subject><subject>Quinoline</subject><subject>Quinolines - chemical synthesis</subject><subject>Quinolines - chemistry</subject><subject>Quinolines - pharmacokinetics</subject><subject>Quinolines - pharmacology</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Structure-Activity Relationship</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkM-r1DAQx4MovvXpP-BBchFPXSdpmrTgRd7zFzzwsgdPhiSd2izdtma6C_3vzbKr3hQmBIbPfJn5MPZSwFaA0G_3W38Iw1ZCboDJpR-xjVBaFaWC6jHbQKOhqBv17YY9I9oDCAVKPWU3Egw0lTIb9n3XI28jhemEaeVubDmt49IjReJTx_v4ox9WPk8Ljguno1_WGTnhgGGJJ-RzP1F-bURaMDlCru55HPvo4zIles6edG4gfHH9b9nu44fd3efi4eunL3fvH4qghFmKrjFal9KXILXQugHXGV-BbJySugXpTBkqU4m2VJUu0dcevaxV8Dp0jWvLW_bmEjun6ecxr2IP-SQcBjfidCSbb61MbSr4L2kqBUJkU5mUFzKkiShhZ-cUDy6tVoA9-7d7e_Zvz_4tmFw6D726xh_9Ads_I7-FZ-D1FXAU3NAlN4ZIf7lSqlo256B3Fw6ztVPEZClEHAO2MWX1tp3iv_b4BZxppB4</recordid><startdate>20100915</startdate><enddate>20100915</enddate><creator>Aspiotis, Renee</creator><creator>Deschênes, Denis</creator><creator>Dubé, Daniel</creator><creator>Girard, Yves</creator><creator>Huang, Zheng</creator><creator>Laliberté, France</creator><creator>Liu, Susana</creator><creator>Papp, Robert</creator><creator>Nicholson, Donald W.</creator><creator>Young, Robert N.</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><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20100915</creationdate><title>The discovery and synthesis of highly potent subtype selective phosphodiesterase 4D inhibitors</title><author>Aspiotis, Renee ; Deschênes, Denis ; Dubé, Daniel ; Girard, Yves ; Huang, Zheng ; Laliberté, France ; Liu, Susana ; Papp, Robert ; Nicholson, Donald W. ; Young, Robert N.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c417t-f976632b302616690af7b5029a426d02a73c5751d34563eb8beb284cb6cf9ad3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Asthma</topic><topic>Asthma - drug therapy</topic><topic>Biological and medical sciences</topic><topic>Bones, joints and connective tissue. Antiinflammatory agents</topic><topic>COPD</topic><topic>Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism</topic><topic>Humans</topic><topic>Inhibitory Concentration 50</topic><topic>Male</topic><topic>Medical sciences</topic><topic>PDE4D</topic><topic>Pharmacokinetics</topic><topic>Pharmacology. 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50
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Animals Asthma Asthma - drug therapy Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents COPD Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism Humans Inhibitory Concentration 50 Male Medical sciences PDE4D Pharmacokinetics Pharmacology. Drug treatments Phosphodiesterase 4D inhibitors Phosphodiesterase Inhibitors - chemical synthesis Phosphodiesterase Inhibitors - chemistry Phosphodiesterase Inhibitors - pharmacokinetics Phosphodiesterase Inhibitors - pharmacology Quinoline Quinolines - chemical synthesis Quinolines - chemistry Quinolines - pharmacokinetics Quinolines - pharmacology Rats Rats, Wistar Structure-Activity Relationship |
| title | The discovery and synthesis of highly potent subtype selective phosphodiesterase 4D inhibitors |
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