Discovery and optimization of 2-phenyloxazole derivatives as diacylglycerol acyltransferase-1 inhibitors
The discovery and SAR studies of a phenyloxazole based diacylglycerol acyltransferase-1 inhibitor are reported. The optimized compound 25 is orally available and demonstrated in vivo efficacy in a diet-induced obesity (DIO) rat model. In a discovery effort to find safe and effective DGAT-1 inhibitor...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2011-12, Vol.21 (23), p.7205-7209 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Yun, Weiya Ahmad, Mushtaq Chen, Yingsi Gillespie, Paul Conde-Knape, Karin Kazmer, Sonja Li, Shiming Qian, Yimin Taub, Rebecca Wertheimer, Stanley J. Whittard, Toni Bolin, David |
| description | The discovery and SAR studies of a phenyloxazole based diacylglycerol acyltransferase-1 inhibitor are reported. The optimized compound
25 is orally available and demonstrated in vivo efficacy in a diet-induced obesity (DIO) rat model.
In a discovery effort to find safe and effective DGAT-1 inhibitors, we have identified 2-phenyloxazole 4-carboxamide
1 as a conformationally constrained analog of a hydrazide hit, which was previously identified from high-throughput screening. Further optimization of this series has led to chemically more stable 2-phenyloxazole-based DGAT-1 inhibitor
25 with improved solubility, cell-based activity, and pharmacokinetic properties. Compound
25 also demonstrated in vivo efficacy in a diet-induced obesity (DIO) rat model. |
| doi_str_mv | 10.1016/j.bmcl.2011.09.039 |
| format | Article |
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25 is orally available and demonstrated in vivo efficacy in a diet-induced obesity (DIO) rat model.
In a discovery effort to find safe and effective DGAT-1 inhibitors, we have identified 2-phenyloxazole 4-carboxamide
1 as a conformationally constrained analog of a hydrazide hit, which was previously identified from high-throughput screening. Further optimization of this series has led to chemically more stable 2-phenyloxazole-based DGAT-1 inhibitor
25 with improved solubility, cell-based activity, and pharmacokinetic properties. Compound
25 also demonstrated in vivo efficacy in a diet-induced obesity (DIO) rat model.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2011.09.039</identifier><identifier>PMID: 22001092</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Administration, Oral ; animal models ; Animals ; Biological and medical sciences ; Body Weight ; DGAT-1 inhibitor ; diacylglycerol acyltransferase ; Diacylglycerol O-Acyltransferase - antagonists & inhibitors ; Diacylglycerol O-Acyltransferase - chemistry ; Disease Models, Animal ; Drug Discovery ; Enzyme Activation - drug effects ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Enzyme Inhibitors - therapeutic use ; General and cellular metabolism. Vitamins ; Humans ; Inhibitory Concentration 50 ; Medical sciences ; Mice ; Molecular Structure ; Obesity ; Obesity - drug therapy ; Oxazoles - chemistry ; Oxazoles - pharmacology ; Oxazoles - therapeutic use ; pharmacokinetics ; Pharmacology. Drug treatments ; Phenyloxazole ; Rats ; screening ; Solubility ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry letters, 2011-12, Vol.21 (23), p.7205-7209</ispartof><rights>2011 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2011 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c473t-c7b79675069ac59e34a8d77ddff0c3c57b4771faca4722e12a1e918441be9a143</citedby><cites>FETCH-LOGICAL-c473t-c7b79675069ac59e34a8d77ddff0c3c57b4771faca4722e12a1e918441be9a143</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X11012832$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24797695$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22001092$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yun, Weiya</creatorcontrib><creatorcontrib>Ahmad, Mushtaq</creatorcontrib><creatorcontrib>Chen, Yingsi</creatorcontrib><creatorcontrib>Gillespie, Paul</creatorcontrib><creatorcontrib>Conde-Knape, Karin</creatorcontrib><creatorcontrib>Kazmer, Sonja</creatorcontrib><creatorcontrib>Li, Shiming</creatorcontrib><creatorcontrib>Qian, Yimin</creatorcontrib><creatorcontrib>Taub, Rebecca</creatorcontrib><creatorcontrib>Wertheimer, Stanley J.</creatorcontrib><creatorcontrib>Whittard, Toni</creatorcontrib><creatorcontrib>Bolin, David</creatorcontrib><title>Discovery and optimization of 2-phenyloxazole derivatives as diacylglycerol acyltransferase-1 inhibitors</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>The discovery and SAR studies of a phenyloxazole based diacylglycerol acyltransferase-1 inhibitor are reported. The optimized compound
25 is orally available and demonstrated in vivo efficacy in a diet-induced obesity (DIO) rat model.
In a discovery effort to find safe and effective DGAT-1 inhibitors, we have identified 2-phenyloxazole 4-carboxamide
1 as a conformationally constrained analog of a hydrazide hit, which was previously identified from high-throughput screening. Further optimization of this series has led to chemically more stable 2-phenyloxazole-based DGAT-1 inhibitor
25 with improved solubility, cell-based activity, and pharmacokinetic properties. Compound
25 also demonstrated in vivo efficacy in a diet-induced obesity (DIO) rat model.</description><subject>Administration, Oral</subject><subject>animal models</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Body Weight</subject><subject>DGAT-1 inhibitor</subject><subject>diacylglycerol acyltransferase</subject><subject>Diacylglycerol O-Acyltransferase - antagonists & inhibitors</subject><subject>Diacylglycerol O-Acyltransferase - chemistry</subject><subject>Disease Models, Animal</subject><subject>Drug Discovery</subject><subject>Enzyme Activation - drug effects</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Enzyme Inhibitors - therapeutic use</subject><subject>General and cellular metabolism. Vitamins</subject><subject>Humans</subject><subject>Inhibitory Concentration 50</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Molecular Structure</subject><subject>Obesity</subject><subject>Obesity - drug therapy</subject><subject>Oxazoles - chemistry</subject><subject>Oxazoles - pharmacology</subject><subject>Oxazoles - therapeutic use</subject><subject>pharmacokinetics</subject><subject>Pharmacology. Drug treatments</subject><subject>Phenyloxazole</subject><subject>Rats</subject><subject>screening</subject><subject>Solubility</subject><subject>Structure-Activity Relationship</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkU2P0zAQhi0EYsvCH-AAuSBOCR7HiWuJC1o-pZU4wErcrIkz2bpy4mKnFdlfj6sWuAEn2_Iz73j8MPYUeAUc2lfbqhutrwQHqLiueK3vsRXIVpa15M19tuK65eVay28X7FFKW85Bcikfsgsh8p5rsWKbty7ZcKC4FDj1RdjNbnR3OLswFWEoRLnb0LT48APvgqeip-gO-fZAqcBU9A7t4m_9YikGXxwPc8QpDRQxUQmFmzauc3OI6TF7MKBP9OS8XrKb9---Xn0srz9_-HT15rq0UtVzaVWndKsa3mq0jaZa4rpXqu-HgdvaNqqTSsGAFqUSgkAgkIa1lNCRRpD1JXt5yt3F8H1PaTZjnpC8x4nCPhkNAE0rlf43yRVoWev1f5CiVWtRt5kUJ9LGkFKkweyiGzEuBrg5SjNbc5RmjtIM1yZLy0XPzvH7bqT-d8kvSxl4cQYwWfRD_mLr0h8uT6Na3WTu-YkbMBi8jZm5-ZI7NTmnbloBmXh9IigrODiKJllHk6XeRbKz6YP720t_ArS_v6A</recordid><startdate>20111201</startdate><enddate>20111201</enddate><creator>Yun, Weiya</creator><creator>Ahmad, Mushtaq</creator><creator>Chen, Yingsi</creator><creator>Gillespie, Paul</creator><creator>Conde-Knape, Karin</creator><creator>Kazmer, Sonja</creator><creator>Li, Shiming</creator><creator>Qian, Yimin</creator><creator>Taub, Rebecca</creator><creator>Wertheimer, Stanley J.</creator><creator>Whittard, Toni</creator><creator>Bolin, David</creator><general>Elsevier Ltd</general><general>Elsevier</general><scope>FBQ</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><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20111201</creationdate><title>Discovery and optimization of 2-phenyloxazole derivatives as diacylglycerol acyltransferase-1 inhibitors</title><author>Yun, Weiya ; Ahmad, Mushtaq ; Chen, Yingsi ; Gillespie, Paul ; Conde-Knape, Karin ; Kazmer, Sonja ; Li, Shiming ; Qian, Yimin ; Taub, Rebecca ; Wertheimer, Stanley J. ; Whittard, Toni ; Bolin, David</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c473t-c7b79675069ac59e34a8d77ddff0c3c57b4771faca4722e12a1e918441be9a143</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Administration, Oral</topic><topic>animal models</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Body Weight</topic><topic>DGAT-1 inhibitor</topic><topic>diacylglycerol acyltransferase</topic><topic>Diacylglycerol O-Acyltransferase - antagonists & inhibitors</topic><topic>Diacylglycerol O-Acyltransferase - chemistry</topic><topic>Disease Models, Animal</topic><topic>Drug Discovery</topic><topic>Enzyme Activation - drug effects</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Enzyme Inhibitors - therapeutic use</topic><topic>General and cellular metabolism. Vitamins</topic><topic>Humans</topic><topic>Inhibitory Concentration 50</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Molecular Structure</topic><topic>Obesity</topic><topic>Obesity - drug therapy</topic><topic>Oxazoles - chemistry</topic><topic>Oxazoles - pharmacology</topic><topic>Oxazoles - therapeutic use</topic><topic>pharmacokinetics</topic><topic>Pharmacology. 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The optimized compound
25 is orally available and demonstrated in vivo efficacy in a diet-induced obesity (DIO) rat model.
In a discovery effort to find safe and effective DGAT-1 inhibitors, we have identified 2-phenyloxazole 4-carboxamide
1 as a conformationally constrained analog of a hydrazide hit, which was previously identified from high-throughput screening. Further optimization of this series has led to chemically more stable 2-phenyloxazole-based DGAT-1 inhibitor
25 with improved solubility, cell-based activity, and pharmacokinetic properties. Compound
25 also demonstrated in vivo efficacy in a diet-induced obesity (DIO) rat model.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>22001092</pmid><doi>10.1016/j.bmcl.2011.09.039</doi><tpages>5</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2011-12, Vol.21 (23), p.7205-7209 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Administration, Oral animal models Animals Biological and medical sciences Body Weight DGAT-1 inhibitor diacylglycerol acyltransferase Diacylglycerol O-Acyltransferase - antagonists & inhibitors Diacylglycerol O-Acyltransferase - chemistry Disease Models, Animal Drug Discovery Enzyme Activation - drug effects Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Enzyme Inhibitors - therapeutic use General and cellular metabolism. Vitamins Humans Inhibitory Concentration 50 Medical sciences Mice Molecular Structure Obesity Obesity - drug therapy Oxazoles - chemistry Oxazoles - pharmacology Oxazoles - therapeutic use pharmacokinetics Pharmacology. Drug treatments Phenyloxazole Rats screening Solubility Structure-Activity Relationship |
| title | Discovery and optimization of 2-phenyloxazole derivatives as diacylglycerol acyltransferase-1 inhibitors |
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