Synthesis and Structure–Activity Relationships of Pyrazolo[1,5-a]pyridine Derivatives: Potent and Orally Active Antagonists of Corticotropin-Releasing Factor 1 Receptor
Design, synthesis, and structure–activity relationships of a series of 3-dialkylamino-7-phenyl pyrazolo[1,5-a]pyridines (I) as selective antagonists of the corticotropin-releasing factor 1 (CRF1) receptor are described. The most prominent compound to emerge from this work, 46 (E2508), exhibits poten...
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| Veröffentlicht in: | Journal of medicinal chemistry 2012-06, Vol.55 (11), p.5255-5269 |
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| container_end_page | 5269 |
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| container_issue | 11 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 55 |
| creator | Takahashi, Yoshinori Hibi, Shigeki Hoshino, Yorihisa Kikuchi, Koichi Shin, Kogyoku Murata-Tai, Kaoru Fujisawa, Masae Ino, Mitsuhiro Shibata, Hisashi Yonaga, Masahiro |
| description | Design, synthesis, and structure–activity relationships of a series of 3-dialkylamino-7-phenyl pyrazolo[1,5-a]pyridines (I) as selective antagonists of the corticotropin-releasing factor 1 (CRF1) receptor are described. The most prominent compound to emerge from this work, 46 (E2508), exhibits potent in vitro activity, excellent drug-like properties, and robust oral efficacy in animal models of stress-related disorders. It has advanced into clinical trials. |
| doi_str_mv | 10.1021/jm300259r |
| format | Article |
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The most prominent compound to emerge from this work, 46 (E2508), exhibits potent in vitro activity, excellent drug-like properties, and robust oral efficacy in animal models of stress-related disorders. 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Med. Chem</addtitle><description>Design, synthesis, and structure–activity relationships of a series of 3-dialkylamino-7-phenyl pyrazolo[1,5-a]pyridines (I) as selective antagonists of the corticotropin-releasing factor 1 (CRF1) receptor are described. The most prominent compound to emerge from this work, 46 (E2508), exhibits potent in vitro activity, excellent drug-like properties, and robust oral efficacy in animal models of stress-related disorders. It has advanced into clinical trials.</description><subject>Administration, Oral</subject><subject>Animals</subject><subject>Antidepressive Agents - chemical synthesis</subject><subject>Antidepressive Agents - pharmacokinetics</subject><subject>Antidepressive Agents - pharmacology</subject><subject>Biological Availability</subject><subject>Cyclic AMP - biosynthesis</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Microsomes, Liver - metabolism</subject><subject>Pyrazoles - chemical synthesis</subject><subject>Pyrazoles - pharmacokinetics</subject><subject>Pyrazoles - pharmacology</subject><subject>Pyridines - chemical synthesis</subject><subject>Pyridines - pharmacokinetics</subject><subject>Pyridines - pharmacology</subject><subject>Receptors, Corticotropin-Releasing Hormone - antagonists & inhibitors</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkc9qFEEQhxsxmDV68AWkL0IER7tq_m17WzaJBgIJRk8iQ29PTdLLbPfY3bMwOfkOvoWP5ZPY7sacPFVRfHw_qoqxFyDegkB4t97kQmAp_SM2gxJFVsxF8ZjN0hAzrDA_ZE9DWAshcsD8CTtELOd1UeQz9ut6svGWgglc2ZZfRz_qOHr6_ePnQkezNXHin6hX0Tgbbs0QuOv41eTVnevdV3hTZurbMHnTGkv8hLzZJnRL4T2_cpFs3Fkvver7ie-ExBc2qhtnTYg72dL5aLSL3g3GZimLVDD2hp8pHZ3nkOI1Dal9xg461Qd6fl-P2Jez08_Lj9nF5Yfz5eIiUzmUMUMAhXJVyEoUFa5aRE01gpRFpSuJXauqrgZcaSmgJACUQpLAWqlWyBJ1fsSO997Bu-8jhdhsTNDU98qSG0OTTi7mOdQ1JPT1HtXeheCpawZvNspPCfrLQfPwmsS-vNeOqw21D-S_XyTg1R5QOjRrN3qbtvyP6A-yfZjI</recordid><startdate>20120614</startdate><enddate>20120614</enddate><creator>Takahashi, Yoshinori</creator><creator>Hibi, Shigeki</creator><creator>Hoshino, Yorihisa</creator><creator>Kikuchi, Koichi</creator><creator>Shin, Kogyoku</creator><creator>Murata-Tai, Kaoru</creator><creator>Fujisawa, Masae</creator><creator>Ino, Mitsuhiro</creator><creator>Shibata, Hisashi</creator><creator>Yonaga, Masahiro</creator><general>American Chemical Society</general><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>20120614</creationdate><title>Synthesis and Structure–Activity Relationships of Pyrazolo[1,5-a]pyridine Derivatives: Potent and Orally Active Antagonists of Corticotropin-Releasing Factor 1 Receptor</title><author>Takahashi, Yoshinori ; Hibi, Shigeki ; Hoshino, Yorihisa ; Kikuchi, Koichi ; Shin, Kogyoku ; Murata-Tai, Kaoru ; Fujisawa, Masae ; Ino, Mitsuhiro ; Shibata, Hisashi ; Yonaga, Masahiro</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a315t-211a29b4960462bd22ce7219946c692fda6f712bc9015e112909e027aad0952c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Administration, Oral</topic><topic>Animals</topic><topic>Antidepressive Agents - chemical synthesis</topic><topic>Antidepressive Agents - pharmacokinetics</topic><topic>Antidepressive Agents - pharmacology</topic><topic>Biological Availability</topic><topic>Cyclic AMP - biosynthesis</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Microsomes, Liver - metabolism</topic><topic>Pyrazoles - chemical synthesis</topic><topic>Pyrazoles - pharmacokinetics</topic><topic>Pyrazoles - pharmacology</topic><topic>Pyridines - chemical synthesis</topic><topic>Pyridines - pharmacokinetics</topic><topic>Pyridines - pharmacology</topic><topic>Receptors, Corticotropin-Releasing Hormone - antagonists & inhibitors</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Takahashi, Yoshinori</creatorcontrib><creatorcontrib>Hibi, Shigeki</creatorcontrib><creatorcontrib>Hoshino, Yorihisa</creatorcontrib><creatorcontrib>Kikuchi, Koichi</creatorcontrib><creatorcontrib>Shin, Kogyoku</creatorcontrib><creatorcontrib>Murata-Tai, Kaoru</creatorcontrib><creatorcontrib>Fujisawa, Masae</creatorcontrib><creatorcontrib>Ino, Mitsuhiro</creatorcontrib><creatorcontrib>Shibata, Hisashi</creatorcontrib><creatorcontrib>Yonaga, Masahiro</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>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Takahashi, Yoshinori</au><au>Hibi, Shigeki</au><au>Hoshino, Yorihisa</au><au>Kikuchi, Koichi</au><au>Shin, Kogyoku</au><au>Murata-Tai, Kaoru</au><au>Fujisawa, Masae</au><au>Ino, Mitsuhiro</au><au>Shibata, Hisashi</au><au>Yonaga, Masahiro</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and Structure–Activity Relationships of Pyrazolo[1,5-a]pyridine Derivatives: Potent and Orally Active Antagonists of Corticotropin-Releasing Factor 1 Receptor</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. 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| subjects | Administration, Oral Animals Antidepressive Agents - chemical synthesis Antidepressive Agents - pharmacokinetics Antidepressive Agents - pharmacology Biological Availability Cyclic AMP - biosynthesis HEK293 Cells Humans Male Mice Mice, Inbred BALB C Microsomes, Liver - metabolism Pyrazoles - chemical synthesis Pyrazoles - pharmacokinetics Pyrazoles - pharmacology Pyridines - chemical synthesis Pyridines - pharmacokinetics Pyridines - pharmacology Receptors, Corticotropin-Releasing Hormone - antagonists & inhibitors Structure-Activity Relationship |
| title | Synthesis and Structure–Activity Relationships of Pyrazolo[1,5-a]pyridine Derivatives: Potent and Orally Active Antagonists of Corticotropin-Releasing Factor 1 Receptor |
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