The synthesis and biological evaluation of a novel series of indole PDE4 inhibitors I
This communication describes the synthesis and in vitro evaluation of a novel potent series of phosphodiesterase type (IV) (PDE4) inhibitors. The compounds described contain an indole moiety which replaces the ‘rolipram-like’ 3-methoxy-4-cyclopentoxy motif. Several of the compounds presented possess...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 1998-07, Vol.8 (14), p.1867-1872 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Hulme, Christopher Moriarty, Kevin Miller, Bruce Mathew, Rose Ramanjulu, Mercy Cox, Paul Souness, John Page, Ken M. Uhl, Joanne Travis, Jeffrey Huang, Fu-chih Labaudiniere, Richard Djuric, Stevan W. |
| description | This communication describes the synthesis and in vitro evaluation of a novel potent series of phosphodiesterase type (IV) (PDE4) inhibitors. The compounds described contain an indole moiety which replaces the ‘rolipram-like’ 3-methoxy-4-cyclopentoxy motif. Several of the compounds presented possess low nanomolar IC
50's for PDEIV inhibition. In vivo activities determined from measurement of serum TNF-α levels in LPS challenged mice (mouse endotoxemia model) are also reported.
The synthesis, in vitro and in vivo evaluation of a novel potent series of indole phosphodiesterase type (IV) (PDE4) inhibitors
1 is presented. Several of the indoles presented possess low nanomolar IC
50's for PDE4 inhibition. The results demonstrate that the indole is an effective isostere for the 3-methoxy 4-cyclopentoxy motif commonly observed in ‘rolipram-like’ PDE4 inhibitors. |
| doi_str_mv | 10.1016/S0960-894X(98)00324-2 |
| format | Article |
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50's for PDEIV inhibition. In vivo activities determined from measurement of serum TNF-α levels in LPS challenged mice (mouse endotoxemia model) are also reported.
The synthesis, in vitro and in vivo evaluation of a novel potent series of indole phosphodiesterase type (IV) (PDE4) inhibitors
1 is presented. Several of the indoles presented possess low nanomolar IC
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50's for PDEIV inhibition. In vivo activities determined from measurement of serum TNF-α levels in LPS challenged mice (mouse endotoxemia model) are also reported.
The synthesis, in vitro and in vivo evaluation of a novel potent series of indole phosphodiesterase type (IV) (PDE4) inhibitors
1 is presented. Several of the indoles presented possess low nanomolar IC
50's for PDE4 inhibition. The results demonstrate that the indole is an effective isostere for the 3-methoxy 4-cyclopentoxy motif commonly observed in ‘rolipram-like’ PDE4 inhibitors.</description><subject>3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Biological Availability</subject><subject>Cyclic Nucleotide Phosphodiesterases, Type 4</subject><subject>Drug Evaluation</subject><subject>Immunomodulators</subject><subject>Indoles - chemical synthesis</subject><subject>Indoles - pharmacokinetics</subject><subject>Indoles - pharmacology</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Pharmacology. Drug treatments</subject><subject>Phosphodiesterase Inhibitors - chemical synthesis</subject><subject>Phosphodiesterase Inhibitors - pharmacokinetics</subject><subject>Phosphodiesterase Inhibitors - pharmacology</subject><subject>Pyrrolidinones - pharmacology</subject><subject>Rolipram</subject><subject>Structure-Activity Relationship</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1998</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkF1rFDEUhoModa3-hEIuRPRi9GTyMcmVSK1aKCjYgnchk5xxI7OTmjO70H_vbHfZW68S8j7nIw9jFwLeCxDmw09wBhrr1K-3zr4DkK1q2idsJZRRjVSgn7LVCXnOXhD9ARAKlDpjZ852Uim3Yne3a-T0MM1rpEw8TIn3uYzld45h5LgL4zbMuUy8DDzwqexw5IQ1I-1f8pTKiPzH5yu13Ne5z3OpxK9fsmdDGAlfHc9zdvfl6vbyW3Pz_ev15aebJkrr5kYHl3rsQxps7Jwclm8Z0UtlddfqAN1ghNStg9AZlNqAs4ipBQsy6n5ISZ6zN4e-97X83SLNfpMp4jiGCcuWvHFCGGlgAfUBjLUQVRz8fc2bUB-8AL_X6R91-r0r76x_1Onbpe7iOGDbbzCdqo7-lvz1MQ-0CBtqmGKmE9ZKqZXct_l4wHCRsctYPcWMU8SUK8bZp5L_s8g_oGqREA</recordid><startdate>19980721</startdate><enddate>19980721</enddate><creator>Hulme, Christopher</creator><creator>Moriarty, Kevin</creator><creator>Miller, Bruce</creator><creator>Mathew, Rose</creator><creator>Ramanjulu, Mercy</creator><creator>Cox, Paul</creator><creator>Souness, John</creator><creator>Page, Ken M.</creator><creator>Uhl, Joanne</creator><creator>Travis, Jeffrey</creator><creator>Huang, Fu-chih</creator><creator>Labaudiniere, Richard</creator><creator>Djuric, Stevan W.</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></search><sort><creationdate>19980721</creationdate><title>The synthesis and biological evaluation of a novel series of indole PDE4 inhibitors I</title><author>Hulme, Christopher ; Moriarty, Kevin ; Miller, Bruce ; Mathew, Rose ; Ramanjulu, Mercy ; Cox, Paul ; Souness, John ; Page, Ken M. ; Uhl, Joanne ; Travis, Jeffrey ; Huang, Fu-chih ; Labaudiniere, Richard ; Djuric, Stevan W.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c389t-5a9dbebadf8c793f01661b3485725a07f6135290a76e356098eed20803c5bfdd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1998</creationdate><topic>3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Biological Availability</topic><topic>Cyclic Nucleotide Phosphodiesterases, Type 4</topic><topic>Drug Evaluation</topic><topic>Immunomodulators</topic><topic>Indoles - chemical synthesis</topic><topic>Indoles - pharmacokinetics</topic><topic>Indoles - pharmacology</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Pharmacology. Drug treatments</topic><topic>Phosphodiesterase Inhibitors - chemical synthesis</topic><topic>Phosphodiesterase Inhibitors - pharmacokinetics</topic><topic>Phosphodiesterase Inhibitors - pharmacology</topic><topic>Pyrrolidinones - pharmacology</topic><topic>Rolipram</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hulme, Christopher</creatorcontrib><creatorcontrib>Moriarty, Kevin</creatorcontrib><creatorcontrib>Miller, Bruce</creatorcontrib><creatorcontrib>Mathew, Rose</creatorcontrib><creatorcontrib>Ramanjulu, Mercy</creatorcontrib><creatorcontrib>Cox, Paul</creatorcontrib><creatorcontrib>Souness, John</creatorcontrib><creatorcontrib>Page, Ken M.</creatorcontrib><creatorcontrib>Uhl, Joanne</creatorcontrib><creatorcontrib>Travis, Jeffrey</creatorcontrib><creatorcontrib>Huang, Fu-chih</creatorcontrib><creatorcontrib>Labaudiniere, Richard</creatorcontrib><creatorcontrib>Djuric, Stevan W.</creatorcontrib><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>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hulme, Christopher</au><au>Moriarty, Kevin</au><au>Miller, Bruce</au><au>Mathew, Rose</au><au>Ramanjulu, Mercy</au><au>Cox, Paul</au><au>Souness, John</au><au>Page, Ken M.</au><au>Uhl, Joanne</au><au>Travis, Jeffrey</au><au>Huang, Fu-chih</au><au>Labaudiniere, Richard</au><au>Djuric, Stevan W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The synthesis and biological evaluation of a novel series of indole PDE4 inhibitors I</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>1998-07-21</date><risdate>1998</risdate><volume>8</volume><issue>14</issue><spage>1867</spage><epage>1872</epage><pages>1867-1872</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>This communication describes the synthesis and in vitro evaluation of a novel potent series of phosphodiesterase type (IV) (PDE4) inhibitors. The compounds described contain an indole moiety which replaces the ‘rolipram-like’ 3-methoxy-4-cyclopentoxy motif. Several of the compounds presented possess low nanomolar IC
50's for PDEIV inhibition. In vivo activities determined from measurement of serum TNF-α levels in LPS challenged mice (mouse endotoxemia model) are also reported.
The synthesis, in vitro and in vivo evaluation of a novel potent series of indole phosphodiesterase type (IV) (PDE4) inhibitors
1 is presented. Several of the indoles presented possess low nanomolar IC
50's for PDE4 inhibition. The results demonstrate that the indole is an effective isostere for the 3-methoxy 4-cyclopentoxy motif commonly observed in ‘rolipram-like’ PDE4 inhibitors.</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>9873449</pmid><doi>10.1016/S0960-894X(98)00324-2</doi><tpages>6</tpages></addata></record> |
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| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 1998-07, Vol.8 (14), p.1867-1872 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors Animals Biological and medical sciences Biological Availability Cyclic Nucleotide Phosphodiesterases, Type 4 Drug Evaluation Immunomodulators Indoles - chemical synthesis Indoles - pharmacokinetics Indoles - pharmacology Medical sciences Mice Pharmacology. Drug treatments Phosphodiesterase Inhibitors - chemical synthesis Phosphodiesterase Inhibitors - pharmacokinetics Phosphodiesterase Inhibitors - pharmacology Pyrrolidinones - pharmacology Rolipram Structure-Activity Relationship |
| title | The synthesis and biological evaluation of a novel series of indole PDE4 inhibitors I |
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