Azetidinones as vasopressin V1a antagonists
The azetidinone LY307174 ( 1) was identified as a screening lead for the vasopressin V1a receptor (IC 50 45 nM at the human V1a receptor) based on molecular similarity to ketoconazole ( 2), a known antagonist of the luteinizing hormone releasing hormone receptor. Structure–activity relationships for...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2007-03, Vol.15 (5), p.2054-2080 |
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| creator | Guillon, Christophe D. Koppel, Gary A. Brownstein, Michael J. Chaney, Michael O. Ferris, Craig F. Lu, Shi-fang Fabio, Karine M. Miller, Marvin J. Heindel, Ned D. Hunden, David C. Cooper, Robin D.G. Kaldor, Stephen W. Skelton, Jeffrey J. Dressman, Bruce A. Clay, Michael P. Steinberg, Mitchell I. Bruns, Robert F. Simon, Neal G. |
| description | The azetidinone LY307174 (
1) was identified as a screening lead for the vasopressin V1a receptor (IC
50 45
nM at the human V1a receptor) based on molecular similarity to ketoconazole (
2), a known antagonist of the luteinizing hormone releasing hormone receptor. Structure–activity relationships for the series were explored to optimize receptor affinity and pharmacokinetic properties, resulting in compounds with
K
i values |
| doi_str_mv | 10.1016/j.bmc.2006.12.031 |
| format | Article |
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1) was identified as a screening lead for the vasopressin V1a receptor (IC
50 45
nM at the human V1a receptor) based on molecular similarity to ketoconazole (
2), a known antagonist of the luteinizing hormone releasing hormone receptor. Structure–activity relationships for the series were explored to optimize receptor affinity and pharmacokinetic properties, resulting in compounds with
K
i values <1
nM and brain levels after oral dosing ∼100-fold higher than receptor affinities.
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1) was identified as a screening lead for the vasopressin V1a receptor (IC
50 45
nM at the human V1a receptor) based on molecular similarity to ketoconazole (
2), a known antagonist of the luteinizing hormone releasing hormone receptor. Structure–activity relationships for the series were explored to optimize receptor affinity and pharmacokinetic properties, resulting in compounds with
K
i values <1
nM and brain levels after oral dosing ∼100-fold higher than receptor affinities.
[Display omitted]</description><subject>Animals</subject><subject>Antidiuretic Hormone Receptor Antagonists</subject><subject>Azetidines - blood</subject><subject>Azetidines - pharmacokinetics</subject><subject>Azetidines - pharmacology</subject><subject>Azetidinone</subject><subject>Biological and medical sciences</subject><subject>Brain - metabolism</subject><subject>CHO Cells</subject><subject>CNS penetration</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>Dogs</subject><subject>Hormones. Endocrine system</subject><subject>Humans</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>Neuropharmacology</subject><subject>Neurotransmitters. Neurotransmission. Receptors</subject><subject>Oral bioavailability</subject><subject>Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems</subject><subject>Pharmacology. Drug treatments</subject><subject>Rats</subject><subject>Spectrometry, Mass, Fast Atom Bombardment</subject><subject>Vasopressin</subject><subject>Vasopressin V1a antagonists</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE2LFDEQhoMo7uzqD_Aic9HL0m1VOslMEBaWxS9Y8LJ4Del09ZqhJxlTPQP6680yg6sXT3Wo532reIR4hdAioHm3afttaCWAaVG20OETsUBlVNN1Fp-KBVizbmBtzZk4Z94AgFQWn4szXMlOKbQLcXn9i-Y4xJQT8dLz8uA57woxx7T8hn7p0-zvc4o88wvxbPQT08vTvBB3Hz_c3Xxubr9--nJzfdsEjTA3_crawYym01KHXtNA1NGgrUepzBgM-KBGiT0ZDXbUOiii1WiAMIxoh-5CXB1rd_t-S0OgNBc_uV2JW19-uuyj-3eT4nd3nw9OgqmnZS14eyoo-ceeeHbbyIGmySfKe3ZojTSq0xXEIxhKZi40_jmC4B4Mu42rht2DYYfSVcM18_rv7x4TJ6UVeHMCPAc_jcWnEPmRW2spVwCVe3_kqKo8RCqOQ6QUaIiFwuyGHP_zxm9BAJnc</recordid><startdate>20070301</startdate><enddate>20070301</enddate><creator>Guillon, Christophe D.</creator><creator>Koppel, Gary A.</creator><creator>Brownstein, Michael J.</creator><creator>Chaney, Michael O.</creator><creator>Ferris, Craig F.</creator><creator>Lu, Shi-fang</creator><creator>Fabio, Karine M.</creator><creator>Miller, Marvin J.</creator><creator>Heindel, Ned D.</creator><creator>Hunden, David C.</creator><creator>Cooper, Robin D.G.</creator><creator>Kaldor, Stephen W.</creator><creator>Skelton, Jeffrey J.</creator><creator>Dressman, Bruce A.</creator><creator>Clay, Michael P.</creator><creator>Steinberg, Mitchell I.</creator><creator>Bruns, Robert F.</creator><creator>Simon, Neal G.</creator><general>Elsevier Ltd</general><general>Elsevier Science</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>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>5PM</scope></search><sort><creationdate>20070301</creationdate><title>Azetidinones as vasopressin V1a antagonists</title><author>Guillon, Christophe D. ; Koppel, Gary A. ; Brownstein, Michael J. ; Chaney, Michael O. ; Ferris, Craig F. ; Lu, Shi-fang ; Fabio, Karine M. ; Miller, Marvin J. ; Heindel, Ned D. ; Hunden, David C. ; Cooper, Robin D.G. ; Kaldor, Stephen W. ; Skelton, Jeffrey J. ; Dressman, Bruce A. ; Clay, Michael P. ; Steinberg, Mitchell I. ; Bruns, Robert F. ; Simon, Neal G.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c510t-b799d6f63525cb5edee3ed59a1246fc60ac4f21be6509f55c4ee7f60e1cf19d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Animals</topic><topic>Antidiuretic Hormone Receptor Antagonists</topic><topic>Azetidines - blood</topic><topic>Azetidines - pharmacokinetics</topic><topic>Azetidines - pharmacology</topic><topic>Azetidinone</topic><topic>Biological and medical sciences</topic><topic>Brain - metabolism</topic><topic>CHO Cells</topic><topic>CNS penetration</topic><topic>Cricetinae</topic><topic>Cricetulus</topic><topic>Dogs</topic><topic>Hormones. Endocrine system</topic><topic>Humans</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Medical sciences</topic><topic>Models, Molecular</topic><topic>Neuropharmacology</topic><topic>Neurotransmitters. Neurotransmission. Receptors</topic><topic>Oral bioavailability</topic><topic>Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems</topic><topic>Pharmacology. Drug treatments</topic><topic>Rats</topic><topic>Spectrometry, Mass, Fast Atom Bombardment</topic><topic>Vasopressin</topic><topic>Vasopressin V1a antagonists</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Guillon, Christophe D.</creatorcontrib><creatorcontrib>Koppel, Gary A.</creatorcontrib><creatorcontrib>Brownstein, Michael J.</creatorcontrib><creatorcontrib>Chaney, Michael O.</creatorcontrib><creatorcontrib>Ferris, Craig F.</creatorcontrib><creatorcontrib>Lu, Shi-fang</creatorcontrib><creatorcontrib>Fabio, Karine M.</creatorcontrib><creatorcontrib>Miller, Marvin J.</creatorcontrib><creatorcontrib>Heindel, Ned D.</creatorcontrib><creatorcontrib>Hunden, David C.</creatorcontrib><creatorcontrib>Cooper, Robin D.G.</creatorcontrib><creatorcontrib>Kaldor, Stephen W.</creatorcontrib><creatorcontrib>Skelton, Jeffrey J.</creatorcontrib><creatorcontrib>Dressman, Bruce A.</creatorcontrib><creatorcontrib>Clay, Michael P.</creatorcontrib><creatorcontrib>Steinberg, Mitchell I.</creatorcontrib><creatorcontrib>Bruns, Robert F.</creatorcontrib><creatorcontrib>Simon, Neal G.</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>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Guillon, Christophe D.</au><au>Koppel, Gary A.</au><au>Brownstein, Michael J.</au><au>Chaney, Michael O.</au><au>Ferris, Craig F.</au><au>Lu, Shi-fang</au><au>Fabio, Karine M.</au><au>Miller, Marvin J.</au><au>Heindel, Ned D.</au><au>Hunden, David C.</au><au>Cooper, Robin D.G.</au><au>Kaldor, Stephen W.</au><au>Skelton, Jeffrey J.</au><au>Dressman, Bruce A.</au><au>Clay, Michael P.</au><au>Steinberg, Mitchell I.</au><au>Bruns, Robert F.</au><au>Simon, Neal G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Azetidinones as vasopressin V1a antagonists</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2007-03-01</date><risdate>2007</risdate><volume>15</volume><issue>5</issue><spage>2054</spage><epage>2080</epage><pages>2054-2080</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>The azetidinone LY307174 (
1) was identified as a screening lead for the vasopressin V1a receptor (IC
50 45
nM at the human V1a receptor) based on molecular similarity to ketoconazole (
2), a known antagonist of the luteinizing hormone releasing hormone receptor. Structure–activity relationships for the series were explored to optimize receptor affinity and pharmacokinetic properties, resulting in compounds with
K
i values <1
nM and brain levels after oral dosing ∼100-fold higher than receptor affinities.
[Display omitted]</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>17234419</pmid><doi>10.1016/j.bmc.2006.12.031</doi><tpages>27</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0968-0896 |
| ispartof | Bioorganic & medicinal chemistry, 2007-03, Vol.15 (5), p.2054-2080 |
| issn | 0968-0896 1464-3391 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2067992 |
| source | MEDLINE; ScienceDirect Journals (5 years ago - present) |
| subjects | Animals Antidiuretic Hormone Receptor Antagonists Azetidines - blood Azetidines - pharmacokinetics Azetidines - pharmacology Azetidinone Biological and medical sciences Brain - metabolism CHO Cells CNS penetration Cricetinae Cricetulus Dogs Hormones. Endocrine system Humans Magnetic Resonance Spectroscopy Medical sciences Models, Molecular Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Oral bioavailability Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems Pharmacology. Drug treatments Rats Spectrometry, Mass, Fast Atom Bombardment Vasopressin Vasopressin V1a antagonists |
| title | Azetidinones as vasopressin V1a antagonists |
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