Synthesis and SAR of 2-Aryloxy-4-alkoxy-pyridines as Potent Orally Active Corticotropin-Releasing Factor 1 Receptor Antagonists
A series of 2-aryloxy-4-alkoxy-pyridines (1) was identified as novel, selective, and orally active antagonists of the corticotropin-releasing factor 1 (CRF1) receptor. Among these, compound 2 (CP-316311) is a potent and selective CRF1 receptor antagonist with an IC50 value of 6.8 nM in receptor bind...
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| Veröffentlicht in: | Journal of medicinal chemistry 2008-03, Vol.51 (5), p.1377-1384 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 51 |
| creator | Chen, Yuhpyng L Braselton, John Forman, James Gallaschun, Randall J Mansbach, Robert Schmidt, Anne W Seeger, Thomas F Sprouse, Jeff S Tingley, F. David Winston, Elizabeth Schulz, David W |
| description | A series of 2-aryloxy-4-alkoxy-pyridines (1) was identified as novel, selective, and orally active antagonists of the corticotropin-releasing factor 1 (CRF1) receptor. Among these, compound 2 (CP-316311) is a potent and selective CRF1 receptor antagonist with an IC50 value of 6.8 nM in receptor binding and demonstrates oral efficacy in central nervous system (CNS) in vivo models. The regiochemistry of compounds in this series was determined by an X-ray structural analysis. A method to control regioselectivity via pyridine-N-oxides was developed. The synthesis of compounds in series 1 (Figure ) and [3H]-2 as well as the structure−activity relationship (SAR) are discussed. The in vitro, ex vivo, and in vivo properties of representative compounds are described herein. Compound 2 was advanced to phase II depression trials to test the hypothesis that CRF1 antagonists could be used clinically as antidepressant drugs. |
| doi_str_mv | 10.1021/jm070578k |
| format | Article |
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David ; Winston, Elizabeth ; Schulz, David W</creator><creatorcontrib>Chen, Yuhpyng L ; Braselton, John ; Forman, James ; Gallaschun, Randall J ; Mansbach, Robert ; Schmidt, Anne W ; Seeger, Thomas F ; Sprouse, Jeff S ; Tingley, F. David ; Winston, Elizabeth ; Schulz, David W</creatorcontrib><description>A series of 2-aryloxy-4-alkoxy-pyridines (1) was identified as novel, selective, and orally active antagonists of the corticotropin-releasing factor 1 (CRF1) receptor. Among these, compound 2 (CP-316311) is a potent and selective CRF1 receptor antagonist with an IC50 value of 6.8 nM in receptor binding and demonstrates oral efficacy in central nervous system (CNS) in vivo models. The regiochemistry of compounds in this series was determined by an X-ray structural analysis. A method to control regioselectivity via pyridine-N-oxides was developed. The synthesis of compounds in series 1 (Figure ) and [3H]-2 as well as the structure−activity relationship (SAR) are discussed. The in vitro, ex vivo, and in vivo properties of representative compounds are described herein. Compound 2 was advanced to phase II depression trials to test the hypothesis that CRF1 antagonists could be used clinically as antidepressant drugs.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm070578k</identifier><identifier>PMID: 18260619</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Action Potentials - drug effects ; Administration, Oral ; Adrenocorticotropic Hormone - blood ; Animals ; Antidepressive Agents - chemical synthesis ; Antidepressive Agents - chemistry ; Antidepressive Agents - pharmacology ; Autoradiography ; Biological and medical sciences ; Brain - physiology ; Cell Line ; Corticotropin-Releasing Hormone - pharmacology ; Crystallography, X-Ray ; Hormones. Endocrine system ; Humans ; In Vitro Techniques ; Isomerism ; Male ; Medical sciences ; Molecular Structure ; Neuropharmacology ; Neurotransmitters. Neurotransmission. Receptors ; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems ; Pharmacology. Drug treatments ; Pituitary Gland - metabolism ; Pyridines - chemical synthesis ; Pyridines - chemistry ; Pyridines - pharmacology ; Radioligand Assay ; Rats ; Rats, Sprague-Dawley ; Receptors, Corticotropin-Releasing Hormone - antagonists & inhibitors ; Reflex, Startle - drug effects ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2008-03, Vol.51 (5), p.1377-1384</ispartof><rights>Copyright © 2008 American Chemical Society</rights><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a447t-cbb434e43cef63fb7d964dfd37f026097e6e666471f9587417bc14971c3e60663</citedby><cites>FETCH-LOGICAL-a447t-cbb434e43cef63fb7d964dfd37f026097e6e666471f9587417bc14971c3e60663</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm070578k$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm070578k$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>315,782,786,2767,27083,27931,27932,56745,56795</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20174855$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18260619$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Yuhpyng L</creatorcontrib><creatorcontrib>Braselton, John</creatorcontrib><creatorcontrib>Forman, James</creatorcontrib><creatorcontrib>Gallaschun, Randall J</creatorcontrib><creatorcontrib>Mansbach, Robert</creatorcontrib><creatorcontrib>Schmidt, Anne W</creatorcontrib><creatorcontrib>Seeger, Thomas F</creatorcontrib><creatorcontrib>Sprouse, Jeff S</creatorcontrib><creatorcontrib>Tingley, F. David</creatorcontrib><creatorcontrib>Winston, Elizabeth</creatorcontrib><creatorcontrib>Schulz, David W</creatorcontrib><title>Synthesis and SAR of 2-Aryloxy-4-alkoxy-pyridines as Potent Orally Active Corticotropin-Releasing Factor 1 Receptor Antagonists</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A series of 2-aryloxy-4-alkoxy-pyridines (1) was identified as novel, selective, and orally active antagonists of the corticotropin-releasing factor 1 (CRF1) receptor. Among these, compound 2 (CP-316311) is a potent and selective CRF1 receptor antagonist with an IC50 value of 6.8 nM in receptor binding and demonstrates oral efficacy in central nervous system (CNS) in vivo models. The regiochemistry of compounds in this series was determined by an X-ray structural analysis. A method to control regioselectivity via pyridine-N-oxides was developed. The synthesis of compounds in series 1 (Figure ) and [3H]-2 as well as the structure−activity relationship (SAR) are discussed. The in vitro, ex vivo, and in vivo properties of representative compounds are described herein. Compound 2 was advanced to phase II depression trials to test the hypothesis that CRF1 antagonists could be used clinically as antidepressant drugs.</description><subject>Action Potentials - drug effects</subject><subject>Administration, Oral</subject><subject>Adrenocorticotropic Hormone - blood</subject><subject>Animals</subject><subject>Antidepressive Agents - chemical synthesis</subject><subject>Antidepressive Agents - chemistry</subject><subject>Antidepressive Agents - pharmacology</subject><subject>Autoradiography</subject><subject>Biological and medical sciences</subject><subject>Brain - physiology</subject><subject>Cell Line</subject><subject>Corticotropin-Releasing Hormone - pharmacology</subject><subject>Crystallography, X-Ray</subject><subject>Hormones. Endocrine system</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Isomerism</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Molecular Structure</subject><subject>Neuropharmacology</subject><subject>Neurotransmitters. Neurotransmission. Receptors</subject><subject>Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems</subject><subject>Pharmacology. Drug treatments</subject><subject>Pituitary Gland - metabolism</subject><subject>Pyridines - chemical synthesis</subject><subject>Pyridines - chemistry</subject><subject>Pyridines - pharmacology</subject><subject>Radioligand Assay</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, Corticotropin-Releasing Hormone - antagonists & inhibitors</subject><subject>Reflex, Startle - drug effects</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0EGLEzEUB_AgiltXD34ByUXBQzSZZJKZYymuCgu7TCt4C5nMmzXtNBmTVHZOfnWntHQvnvIgP_6890foLaOfGC3Y5-2eKlqqavcMLVhZUCIqKp6jBaVFQQpZ8Cv0KqUtpZSzgr9EV6wqJJWsXqC_68nnX5BcwsZ3eL1scOhxQZZxGsLjRAQxw-44jFN0nfMwu4TvQwaf8V00wzDhpc3uD-BViNnZkGMYnScNDGCS8w_4xtgcIma4AQvjcVz6bB6Cdymn1-hFb4YEb87vNfpx82Wz-kZu775-Xy1viRFCZWLbVnABglvoJe9b1dVSdH3HVU_nU2oFEqSUQrG-LislmGotE7VilsN8qeTX6MMpd4zh9wFS1nuXLAyD8RAOSSvKZa2EmuHHE7QxpBSh12N0exMnzag-tq0vbc_23Tn00O6he5Lnemfw_gxMsmboo_HWpYsrKFOiKsvZkZObK4HHy7-JOy0VV6Xe3K-1aLhoNj-53jzlGpv0Nhyin7v7z4L_AGNrorQ</recordid><startdate>20080313</startdate><enddate>20080313</enddate><creator>Chen, Yuhpyng L</creator><creator>Braselton, John</creator><creator>Forman, James</creator><creator>Gallaschun, Randall J</creator><creator>Mansbach, Robert</creator><creator>Schmidt, Anne W</creator><creator>Seeger, Thomas F</creator><creator>Sprouse, Jeff S</creator><creator>Tingley, F. David</creator><creator>Winston, Elizabeth</creator><creator>Schulz, David W</creator><general>American Chemical Society</general><scope>BSCLL</scope><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>20080313</creationdate><title>Synthesis and SAR of 2-Aryloxy-4-alkoxy-pyridines as Potent Orally Active Corticotropin-Releasing Factor 1 Receptor Antagonists</title><author>Chen, Yuhpyng L ; Braselton, John ; Forman, James ; Gallaschun, Randall J ; Mansbach, Robert ; Schmidt, Anne W ; Seeger, Thomas F ; Sprouse, Jeff S ; Tingley, F. David ; Winston, Elizabeth ; Schulz, David W</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a447t-cbb434e43cef63fb7d964dfd37f026097e6e666471f9587417bc14971c3e60663</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Action Potentials - drug effects</topic><topic>Administration, Oral</topic><topic>Adrenocorticotropic Hormone - blood</topic><topic>Animals</topic><topic>Antidepressive Agents - chemical synthesis</topic><topic>Antidepressive Agents - chemistry</topic><topic>Antidepressive Agents - pharmacology</topic><topic>Autoradiography</topic><topic>Biological and medical sciences</topic><topic>Brain - physiology</topic><topic>Cell Line</topic><topic>Corticotropin-Releasing Hormone - pharmacology</topic><topic>Crystallography, X-Ray</topic><topic>Hormones. Endocrine system</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Isomerism</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Molecular Structure</topic><topic>Neuropharmacology</topic><topic>Neurotransmitters. Neurotransmission. Receptors</topic><topic>Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems</topic><topic>Pharmacology. Drug treatments</topic><topic>Pituitary Gland - metabolism</topic><topic>Pyridines - chemical synthesis</topic><topic>Pyridines - chemistry</topic><topic>Pyridines - pharmacology</topic><topic>Radioligand Assay</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptors, Corticotropin-Releasing Hormone - antagonists & inhibitors</topic><topic>Reflex, Startle - drug effects</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Yuhpyng L</creatorcontrib><creatorcontrib>Braselton, John</creatorcontrib><creatorcontrib>Forman, James</creatorcontrib><creatorcontrib>Gallaschun, Randall J</creatorcontrib><creatorcontrib>Mansbach, Robert</creatorcontrib><creatorcontrib>Schmidt, Anne W</creatorcontrib><creatorcontrib>Seeger, Thomas F</creatorcontrib><creatorcontrib>Sprouse, Jeff S</creatorcontrib><creatorcontrib>Tingley, F. David</creatorcontrib><creatorcontrib>Winston, Elizabeth</creatorcontrib><creatorcontrib>Schulz, David W</creatorcontrib><collection>Istex</collection><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>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Yuhpyng L</au><au>Braselton, John</au><au>Forman, James</au><au>Gallaschun, Randall J</au><au>Mansbach, Robert</au><au>Schmidt, Anne W</au><au>Seeger, Thomas F</au><au>Sprouse, Jeff S</au><au>Tingley, F. David</au><au>Winston, Elizabeth</au><au>Schulz, David W</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and SAR of 2-Aryloxy-4-alkoxy-pyridines as Potent Orally Active Corticotropin-Releasing Factor 1 Receptor Antagonists</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2008-03-13</date><risdate>2008</risdate><volume>51</volume><issue>5</issue><spage>1377</spage><epage>1384</epage><pages>1377-1384</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>A series of 2-aryloxy-4-alkoxy-pyridines (1) was identified as novel, selective, and orally active antagonists of the corticotropin-releasing factor 1 (CRF1) receptor. Among these, compound 2 (CP-316311) is a potent and selective CRF1 receptor antagonist with an IC50 value of 6.8 nM in receptor binding and demonstrates oral efficacy in central nervous system (CNS) in vivo models. The regiochemistry of compounds in this series was determined by an X-ray structural analysis. A method to control regioselectivity via pyridine-N-oxides was developed. The synthesis of compounds in series 1 (Figure ) and [3H]-2 as well as the structure−activity relationship (SAR) are discussed. The in vitro, ex vivo, and in vivo properties of representative compounds are described herein. Compound 2 was advanced to phase II depression trials to test the hypothesis that CRF1 antagonists could be used clinically as antidepressant drugs.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>18260619</pmid><doi>10.1021/jm070578k</doi><tpages>8</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2008-03, Vol.51 (5), p.1377-1384 |
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| subjects | Action Potentials - drug effects Administration, Oral Adrenocorticotropic Hormone - blood Animals Antidepressive Agents - chemical synthesis Antidepressive Agents - chemistry Antidepressive Agents - pharmacology Autoradiography Biological and medical sciences Brain - physiology Cell Line Corticotropin-Releasing Hormone - pharmacology Crystallography, X-Ray Hormones. Endocrine system Humans In Vitro Techniques Isomerism Male Medical sciences Molecular Structure Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems Pharmacology. Drug treatments Pituitary Gland - metabolism Pyridines - chemical synthesis Pyridines - chemistry Pyridines - pharmacology Radioligand Assay Rats Rats, Sprague-Dawley Receptors, Corticotropin-Releasing Hormone - antagonists & inhibitors Reflex, Startle - drug effects Structure-Activity Relationship |
| title | Synthesis and SAR of 2-Aryloxy-4-alkoxy-pyridines as Potent Orally Active Corticotropin-Releasing Factor 1 Receptor Antagonists |
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