Diphenylpyridylethanamine (DPPE) Derivatives as Cholesteryl Ester Transfer Protein (CETP) Inhibitors
A series of diphenylpyridylethanamine (DPPE) derivatives was identified exhibiting potent CETP inhibition. Replacing the labile ester functionality in the initial lead 7 generated a series of amides and ureas. Further optimization of the DPPE series for potency resulted in the discovery of cyclopent...
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| Veröffentlicht in: | Journal of medicinal chemistry 2012-07, Vol.55 (13), p.6162-6175 |
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| container_title | Journal of medicinal chemistry |
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| creator | Harikrishnan, Lalgudi S Finlay, Heather J Qiao, Jennifer X Kamau, Muthoni G Jiang, Ji Wang, Tammy C Li, James Cooper, Christopher B Poss, Michael A Adam, Leonard P Taylor, David S Chen, Alice Ye A Yin, Xiaohong Sleph, Paul G Yang, Richard Z Sitkoff, Doree F Galella, Michael A Nirschl, David S Van Kirk, Katy Miller, Arthur V Huang, Christine S Chang, Ming Chen, Xue-Qing Salvati, Mark E Wexler, Ruth R Lawrence, R. Michael |
| description | A series of diphenylpyridylethanamine (DPPE) derivatives was identified exhibiting potent CETP inhibition. Replacing the labile ester functionality in the initial lead 7 generated a series of amides and ureas. Further optimization of the DPPE series for potency resulted in the discovery of cyclopentylurea 15d, which demonstrated a reduction in cholesterol ester transfer activity (48% of predose level) in hCETP/apoB-100 dual transgenic mice. The PK profile of 15d was suboptimal, and further optimization of the N-terminus resulted in the discovery of amide 20 with an improved PK profile and robust efficacy in transgenic hCETP/apoB-100 mice and in hamsters. Compound 20 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemeterized rats despite sustained high exposures. |
| doi_str_mv | 10.1021/jm300611v |
| format | Article |
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Michael</creator><creatorcontrib>Harikrishnan, Lalgudi S ; Finlay, Heather J ; Qiao, Jennifer X ; Kamau, Muthoni G ; Jiang, Ji ; Wang, Tammy C ; Li, James ; Cooper, Christopher B ; Poss, Michael A ; Adam, Leonard P ; Taylor, David S ; Chen, Alice Ye A ; Yin, Xiaohong ; Sleph, Paul G ; Yang, Richard Z ; Sitkoff, Doree F ; Galella, Michael A ; Nirschl, David S ; Van Kirk, Katy ; Miller, Arthur V ; Huang, Christine S ; Chang, Ming ; Chen, Xue-Qing ; Salvati, Mark E ; Wexler, Ruth R ; Lawrence, R. Michael</creatorcontrib><description>A series of diphenylpyridylethanamine (DPPE) derivatives was identified exhibiting potent CETP inhibition. Replacing the labile ester functionality in the initial lead 7 generated a series of amides and ureas. Further optimization of the DPPE series for potency resulted in the discovery of cyclopentylurea 15d, which demonstrated a reduction in cholesterol ester transfer activity (48% of predose level) in hCETP/apoB-100 dual transgenic mice. The PK profile of 15d was suboptimal, and further optimization of the N-terminus resulted in the discovery of amide 20 with an improved PK profile and robust efficacy in transgenic hCETP/apoB-100 mice and in hamsters. Compound 20 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemeterized rats despite sustained high exposures.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm300611v</identifier><identifier>PMID: 22650305</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Anticholesteremic Agents - chemical synthesis ; Anticholesteremic Agents - chemistry ; Anticholesteremic Agents - pharmacology ; Apolipoprotein B-100 - antagonists & inhibitors ; Apolipoprotein B-100 - metabolism ; Blood Pressure - drug effects ; Cholesterol Ester Transfer Proteins - antagonists & inhibitors ; Cholesterol Ester Transfer Proteins - metabolism ; Coronary Disease - drug therapy ; Cricetinae ; Drug Discovery ; Heart Rate - drug effects ; Humans ; Inhibitory Concentration 50 ; Male ; Mice ; Mice, Transgenic ; Molecular Structure ; Pyridines - chemical synthesis ; Pyridines - chemistry ; Pyridines - pharmacology ; Rats ; Stilbenes - chemical synthesis ; Stilbenes - chemistry ; Stilbenes - pharmacology</subject><ispartof>Journal of medicinal chemistry, 2012-07, Vol.55 (13), p.6162-6175</ispartof><rights>Copyright © 2012 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a315t-3372a8e931c53b6f7e166d7ca7e8bc4b8d6e08de3ceedc8e5fcce8f24c75a8d13</citedby><cites>FETCH-LOGICAL-a315t-3372a8e931c53b6f7e166d7ca7e8bc4b8d6e08de3ceedc8e5fcce8f24c75a8d13</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/jm300611v$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm300611v$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22650305$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Harikrishnan, Lalgudi S</creatorcontrib><creatorcontrib>Finlay, Heather J</creatorcontrib><creatorcontrib>Qiao, Jennifer X</creatorcontrib><creatorcontrib>Kamau, Muthoni G</creatorcontrib><creatorcontrib>Jiang, Ji</creatorcontrib><creatorcontrib>Wang, Tammy C</creatorcontrib><creatorcontrib>Li, James</creatorcontrib><creatorcontrib>Cooper, Christopher B</creatorcontrib><creatorcontrib>Poss, Michael A</creatorcontrib><creatorcontrib>Adam, Leonard P</creatorcontrib><creatorcontrib>Taylor, David S</creatorcontrib><creatorcontrib>Chen, Alice Ye A</creatorcontrib><creatorcontrib>Yin, Xiaohong</creatorcontrib><creatorcontrib>Sleph, Paul G</creatorcontrib><creatorcontrib>Yang, Richard Z</creatorcontrib><creatorcontrib>Sitkoff, Doree F</creatorcontrib><creatorcontrib>Galella, Michael A</creatorcontrib><creatorcontrib>Nirschl, David S</creatorcontrib><creatorcontrib>Van Kirk, Katy</creatorcontrib><creatorcontrib>Miller, Arthur V</creatorcontrib><creatorcontrib>Huang, Christine S</creatorcontrib><creatorcontrib>Chang, Ming</creatorcontrib><creatorcontrib>Chen, Xue-Qing</creatorcontrib><creatorcontrib>Salvati, Mark E</creatorcontrib><creatorcontrib>Wexler, Ruth R</creatorcontrib><creatorcontrib>Lawrence, R. Michael</creatorcontrib><title>Diphenylpyridylethanamine (DPPE) Derivatives as Cholesteryl Ester Transfer Protein (CETP) Inhibitors</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A series of diphenylpyridylethanamine (DPPE) derivatives was identified exhibiting potent CETP inhibition. Replacing the labile ester functionality in the initial lead 7 generated a series of amides and ureas. Further optimization of the DPPE series for potency resulted in the discovery of cyclopentylurea 15d, which demonstrated a reduction in cholesterol ester transfer activity (48% of predose level) in hCETP/apoB-100 dual transgenic mice. The PK profile of 15d was suboptimal, and further optimization of the N-terminus resulted in the discovery of amide 20 with an improved PK profile and robust efficacy in transgenic hCETP/apoB-100 mice and in hamsters. Compound 20 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemeterized rats despite sustained high exposures.</description><subject>Animals</subject><subject>Anticholesteremic Agents - chemical synthesis</subject><subject>Anticholesteremic Agents - chemistry</subject><subject>Anticholesteremic Agents - pharmacology</subject><subject>Apolipoprotein B-100 - antagonists & inhibitors</subject><subject>Apolipoprotein B-100 - metabolism</subject><subject>Blood Pressure - drug effects</subject><subject>Cholesterol Ester Transfer Proteins - antagonists & inhibitors</subject><subject>Cholesterol Ester Transfer Proteins - metabolism</subject><subject>Coronary Disease - drug therapy</subject><subject>Cricetinae</subject><subject>Drug Discovery</subject><subject>Heart Rate - drug effects</subject><subject>Humans</subject><subject>Inhibitory Concentration 50</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Molecular Structure</subject><subject>Pyridines - chemical synthesis</subject><subject>Pyridines - chemistry</subject><subject>Pyridines - pharmacology</subject><subject>Rats</subject><subject>Stilbenes - chemical synthesis</subject><subject>Stilbenes - chemistry</subject><subject>Stilbenes - pharmacology</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>eNpt0D1PwzAQBmALgWgpDPwB5AWpHQL-SJx0RGmASpXIUObIsS-Kq3xhp5Xy70nV0onpbnj06u5F6JGSF0oYfd3VnBBB6eEKTWnAiOdHxL9GU0IY85hgfILunNsRQjhl_BZNGBMB4SSYIr0yXQnNUHWDNXqooC9lI2vTAJ6v0jRZ4BVYc5C9OYDD0uG4bCtwPdihwslx4q2VjSvGJbVtD6bB8zjZpgu8bkqTm7617h7dFLJy8HCeM_T9nmzjT2_z9bGO3zae5DToPc5DJiNYcqoCnosiBCqEDpUMIcqVn0daAIk0cAWgVQRBoRREBfNVGMhIUz5D81NuZ9uf_XhlVhunoKpkA-3eZWNZ_pKLMFyOdHGiyrbOWSiyzppa2mFER0ezS6mjfTrH7vMa9EX-tTiC5xOQymW7dm-b8ct_gn4BIQh-9A</recordid><startdate>20120712</startdate><enddate>20120712</enddate><creator>Harikrishnan, Lalgudi S</creator><creator>Finlay, Heather J</creator><creator>Qiao, Jennifer X</creator><creator>Kamau, Muthoni G</creator><creator>Jiang, Ji</creator><creator>Wang, Tammy C</creator><creator>Li, James</creator><creator>Cooper, Christopher B</creator><creator>Poss, Michael A</creator><creator>Adam, Leonard P</creator><creator>Taylor, David S</creator><creator>Chen, Alice Ye A</creator><creator>Yin, Xiaohong</creator><creator>Sleph, Paul G</creator><creator>Yang, Richard Z</creator><creator>Sitkoff, Doree F</creator><creator>Galella, Michael A</creator><creator>Nirschl, David S</creator><creator>Van Kirk, Katy</creator><creator>Miller, Arthur V</creator><creator>Huang, Christine S</creator><creator>Chang, Ming</creator><creator>Chen, Xue-Qing</creator><creator>Salvati, Mark E</creator><creator>Wexler, Ruth R</creator><creator>Lawrence, R. Michael</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>20120712</creationdate><title>Diphenylpyridylethanamine (DPPE) Derivatives as Cholesteryl Ester Transfer Protein (CETP) Inhibitors</title><author>Harikrishnan, Lalgudi S ; Finlay, Heather J ; Qiao, Jennifer X ; Kamau, Muthoni G ; Jiang, Ji ; Wang, Tammy C ; Li, James ; Cooper, Christopher B ; Poss, Michael A ; Adam, Leonard P ; Taylor, David S ; Chen, Alice Ye A ; Yin, Xiaohong ; Sleph, Paul G ; Yang, Richard Z ; Sitkoff, Doree F ; Galella, Michael A ; Nirschl, David S ; Van Kirk, Katy ; Miller, Arthur V ; Huang, Christine S ; Chang, Ming ; Chen, Xue-Qing ; Salvati, Mark E ; Wexler, Ruth R ; Lawrence, R. 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Michael</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>Harikrishnan, Lalgudi S</au><au>Finlay, Heather J</au><au>Qiao, Jennifer X</au><au>Kamau, Muthoni G</au><au>Jiang, Ji</au><au>Wang, Tammy C</au><au>Li, James</au><au>Cooper, Christopher B</au><au>Poss, Michael A</au><au>Adam, Leonard P</au><au>Taylor, David S</au><au>Chen, Alice Ye A</au><au>Yin, Xiaohong</au><au>Sleph, Paul G</au><au>Yang, Richard Z</au><au>Sitkoff, Doree F</au><au>Galella, Michael A</au><au>Nirschl, David S</au><au>Van Kirk, Katy</au><au>Miller, Arthur V</au><au>Huang, Christine S</au><au>Chang, Ming</au><au>Chen, Xue-Qing</au><au>Salvati, Mark E</au><au>Wexler, Ruth R</au><au>Lawrence, R. Michael</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Diphenylpyridylethanamine (DPPE) Derivatives as Cholesteryl Ester Transfer Protein (CETP) Inhibitors</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2012-07-12</date><risdate>2012</risdate><volume>55</volume><issue>13</issue><spage>6162</spage><epage>6175</epage><pages>6162-6175</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>A series of diphenylpyridylethanamine (DPPE) derivatives was identified exhibiting potent CETP inhibition. Replacing the labile ester functionality in the initial lead 7 generated a series of amides and ureas. Further optimization of the DPPE series for potency resulted in the discovery of cyclopentylurea 15d, which demonstrated a reduction in cholesterol ester transfer activity (48% of predose level) in hCETP/apoB-100 dual transgenic mice. The PK profile of 15d was suboptimal, and further optimization of the N-terminus resulted in the discovery of amide 20 with an improved PK profile and robust efficacy in transgenic hCETP/apoB-100 mice and in hamsters. Compound 20 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemeterized rats despite sustained high exposures.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>22650305</pmid><doi>10.1021/jm300611v</doi><tpages>14</tpages></addata></record> |
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| source | ACS Publications; MEDLINE |
| subjects | Animals Anticholesteremic Agents - chemical synthesis Anticholesteremic Agents - chemistry Anticholesteremic Agents - pharmacology Apolipoprotein B-100 - antagonists & inhibitors Apolipoprotein B-100 - metabolism Blood Pressure - drug effects Cholesterol Ester Transfer Proteins - antagonists & inhibitors Cholesterol Ester Transfer Proteins - metabolism Coronary Disease - drug therapy Cricetinae Drug Discovery Heart Rate - drug effects Humans Inhibitory Concentration 50 Male Mice Mice, Transgenic Molecular Structure Pyridines - chemical synthesis Pyridines - chemistry Pyridines - pharmacology Rats Stilbenes - chemical synthesis Stilbenes - chemistry Stilbenes - pharmacology |
| title | Diphenylpyridylethanamine (DPPE) Derivatives as Cholesteryl Ester Transfer Protein (CETP) Inhibitors |
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