Discovery and synthesis of tetrahydropyrimidinedione-4-carboxamides as endothelial lipase inhibitors
[Display omitted] •A series of tetrahydropyrimidinedione EL inhibitors was identified.•New compounds showed measurable EL inhibition in human serum.•Optimization led to 4a with micromolar human serum potency and 3g with acceptable mouse PK. Endothelial lipase (EL) inhibitors have been shown to eleva...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2018-12, Vol.28 (23-24), p.3721-3725 |
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| creator | Hu, Carol H. Wang, Tammy C. Qiao, Jennifer X. Haque, Lauren Chen, Alice Y.A. Taylor, David S. Ying, Xiaohong Onorato, Joelle M. Galella, Michael Shen, Hong Huang, Christine S. Toussaint, Nathalie Li, Yi-Xin Abell, Lynn Adam, Leonard P. Gordon, David Wexler, Ruth R. Finlay, Heather J. |
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•A series of tetrahydropyrimidinedione EL inhibitors was identified.•New compounds showed measurable EL inhibition in human serum.•Optimization led to 4a with micromolar human serum potency and 3g with acceptable mouse PK.
Endothelial lipase (EL) inhibitors have been shown to elevate HDL-C levels in pre-clinical murine models and have potential benefit in prevention and treatment of cardiovascular diseases. Modification of the 1-ethyl-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one (DHP) lead, 1, led to the discovery of a series of potent tetrahydropyrimidinedione (THP) EL inhibitors. Synthesis and SAR studies including modification of the amide group, together with changes on the pyrimidinone core led to a series of arylcycloalkyl, indanyl, and tetralinyl substituted 5-amino or 5-hydroxypyrimidinedione-4-carboxamides. Several compounds were advanced to PK evaluation. Among them, compound 4a was one of the most potent with measurable ELHDL hSerum potency and compound 3g demonstrated the best overall pharmacokinetic parameters. |
| doi_str_mv | 10.1016/j.bmcl.2018.10.022 |
| format | Article |
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•A series of tetrahydropyrimidinedione EL inhibitors was identified.•New compounds showed measurable EL inhibition in human serum.•Optimization led to 4a with micromolar human serum potency and 3g with acceptable mouse PK.
Endothelial lipase (EL) inhibitors have been shown to elevate HDL-C levels in pre-clinical murine models and have potential benefit in prevention and treatment of cardiovascular diseases. Modification of the 1-ethyl-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one (DHP) lead, 1, led to the discovery of a series of potent tetrahydropyrimidinedione (THP) EL inhibitors. Synthesis and SAR studies including modification of the amide group, together with changes on the pyrimidinone core led to a series of arylcycloalkyl, indanyl, and tetralinyl substituted 5-amino or 5-hydroxypyrimidinedione-4-carboxamides. Several compounds were advanced to PK evaluation. Among them, compound 4a was one of the most potent with measurable ELHDL hSerum potency and compound 3g demonstrated the best overall pharmacokinetic parameters.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2018.10.022</identifier><identifier>PMID: 30348490</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Animals ; Atherosclerosis ; Cholesterol, HDL - blood ; Cholesterol, HDL - metabolism ; Endothelial lipase (EL) inhibitors ; Enzyme Inhibitors - blood ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; High density lipoprotein cholesterol (HDL-C) ; Humans ; Lipase - antagonists & inhibitors ; Lipase - blood ; Lipase - metabolism ; Mice ; Models, Molecular ; Pyrimidinones - blood ; Pyrimidinones - chemical synthesis ; Pyrimidinones - chemistry ; Pyrimidinones - pharmacology ; Structure-Activity Relationship ; Tetrahydropyrimidinedione (THP)</subject><ispartof>Bioorganic & medicinal chemistry letters, 2018-12, Vol.28 (23-24), p.3721-3725</ispartof><rights>2018 Elsevier Ltd</rights><rights>Copyright © 2018 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-ade6f5dcf3ce5f95adb1c611f83d14fece4164fa987e2805796e51f5d03b9c8a3</citedby><cites>FETCH-LOGICAL-c356t-ade6f5dcf3ce5f95adb1c611f83d14fece4164fa987e2805796e51f5d03b9c8a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X18308242$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30348490$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hu, Carol H.</creatorcontrib><creatorcontrib>Wang, Tammy C.</creatorcontrib><creatorcontrib>Qiao, Jennifer X.</creatorcontrib><creatorcontrib>Haque, Lauren</creatorcontrib><creatorcontrib>Chen, Alice Y.A.</creatorcontrib><creatorcontrib>Taylor, David S.</creatorcontrib><creatorcontrib>Ying, Xiaohong</creatorcontrib><creatorcontrib>Onorato, Joelle M.</creatorcontrib><creatorcontrib>Galella, Michael</creatorcontrib><creatorcontrib>Shen, Hong</creatorcontrib><creatorcontrib>Huang, Christine S.</creatorcontrib><creatorcontrib>Toussaint, Nathalie</creatorcontrib><creatorcontrib>Li, Yi-Xin</creatorcontrib><creatorcontrib>Abell, Lynn</creatorcontrib><creatorcontrib>Adam, Leonard P.</creatorcontrib><creatorcontrib>Gordon, David</creatorcontrib><creatorcontrib>Wexler, Ruth R.</creatorcontrib><creatorcontrib>Finlay, Heather J.</creatorcontrib><title>Discovery and synthesis of tetrahydropyrimidinedione-4-carboxamides as endothelial lipase inhibitors</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
•A series of tetrahydropyrimidinedione EL inhibitors was identified.•New compounds showed measurable EL inhibition in human serum.•Optimization led to 4a with micromolar human serum potency and 3g with acceptable mouse PK.
Endothelial lipase (EL) inhibitors have been shown to elevate HDL-C levels in pre-clinical murine models and have potential benefit in prevention and treatment of cardiovascular diseases. Modification of the 1-ethyl-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one (DHP) lead, 1, led to the discovery of a series of potent tetrahydropyrimidinedione (THP) EL inhibitors. Synthesis and SAR studies including modification of the amide group, together with changes on the pyrimidinone core led to a series of arylcycloalkyl, indanyl, and tetralinyl substituted 5-amino or 5-hydroxypyrimidinedione-4-carboxamides. Several compounds were advanced to PK evaluation. Among them, compound 4a was one of the most potent with measurable ELHDL hSerum potency and compound 3g demonstrated the best overall pharmacokinetic parameters.</description><subject>Animals</subject><subject>Atherosclerosis</subject><subject>Cholesterol, HDL - blood</subject><subject>Cholesterol, HDL - metabolism</subject><subject>Endothelial lipase (EL) inhibitors</subject><subject>Enzyme Inhibitors - blood</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>High density lipoprotein cholesterol (HDL-C)</subject><subject>Humans</subject><subject>Lipase - antagonists & inhibitors</subject><subject>Lipase - blood</subject><subject>Lipase - metabolism</subject><subject>Mice</subject><subject>Models, Molecular</subject><subject>Pyrimidinones - blood</subject><subject>Pyrimidinones - chemical synthesis</subject><subject>Pyrimidinones - chemistry</subject><subject>Pyrimidinones - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Tetrahydropyrimidinedione (THP)</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1LxDAYhIMo7rr6BzxIjl5akzbNtuBF_IYFLwreQpq8YbO0TU26i_33puzq0dPAMDMwD0KXlKSUUH6zSetWNWlGaBmNlGTZEZpTxlmSM1IcozmpOEnKin3O0FkIG0IoI4ydollOclayisyRfrBBuR34EctO4zB2wxqCDdgZPMDg5XrU3vWjt63VtgNtXQcJS5T0tfuW0YSAZcDQaRebjZUNbmwvA2DbrW1tB-fDOToxsglwcdAF-nh6fL9_SVZvz6_3d6tE5QUfEqmBm0IrkysoTFVIXVPFKTVlrikzoIBRzoysyiVkJSmWFYeCxgbJ60qVMl-g6_1u793XFsIg2vgOmkZ24LZBZDTjFWUF4zGa7aPKuxA8GNHHi9KPghIx0RUbMdEVE93Ji3Rj6eqwv61b0H-VX5wxcLsPQHy5s-BFUBY6FbF5UIPQzv63_wP8a46H</recordid><startdate>20181215</startdate><enddate>20181215</enddate><creator>Hu, Carol H.</creator><creator>Wang, Tammy C.</creator><creator>Qiao, Jennifer X.</creator><creator>Haque, Lauren</creator><creator>Chen, Alice Y.A.</creator><creator>Taylor, David S.</creator><creator>Ying, Xiaohong</creator><creator>Onorato, Joelle M.</creator><creator>Galella, Michael</creator><creator>Shen, Hong</creator><creator>Huang, Christine S.</creator><creator>Toussaint, Nathalie</creator><creator>Li, Yi-Xin</creator><creator>Abell, Lynn</creator><creator>Adam, Leonard P.</creator><creator>Gordon, David</creator><creator>Wexler, Ruth R.</creator><creator>Finlay, Heather J.</creator><general>Elsevier Ltd</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>20181215</creationdate><title>Discovery and synthesis of tetrahydropyrimidinedione-4-carboxamides as endothelial lipase inhibitors</title><author>Hu, Carol H. ; Wang, Tammy C. ; Qiao, Jennifer X. ; Haque, Lauren ; Chen, Alice Y.A. ; Taylor, David S. ; Ying, Xiaohong ; Onorato, Joelle M. ; Galella, Michael ; Shen, Hong ; Huang, Christine S. ; Toussaint, Nathalie ; Li, Yi-Xin ; Abell, Lynn ; Adam, Leonard P. ; Gordon, David ; Wexler, Ruth R. ; Finlay, Heather J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-ade6f5dcf3ce5f95adb1c611f83d14fece4164fa987e2805796e51f5d03b9c8a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Animals</topic><topic>Atherosclerosis</topic><topic>Cholesterol, HDL - blood</topic><topic>Cholesterol, HDL - metabolism</topic><topic>Endothelial lipase (EL) inhibitors</topic><topic>Enzyme Inhibitors - blood</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>High density lipoprotein cholesterol (HDL-C)</topic><topic>Humans</topic><topic>Lipase - antagonists & inhibitors</topic><topic>Lipase - blood</topic><topic>Lipase - metabolism</topic><topic>Mice</topic><topic>Models, Molecular</topic><topic>Pyrimidinones - blood</topic><topic>Pyrimidinones - chemical synthesis</topic><topic>Pyrimidinones - chemistry</topic><topic>Pyrimidinones - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>Tetrahydropyrimidinedione (THP)</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hu, Carol H.</creatorcontrib><creatorcontrib>Wang, Tammy C.</creatorcontrib><creatorcontrib>Qiao, Jennifer X.</creatorcontrib><creatorcontrib>Haque, Lauren</creatorcontrib><creatorcontrib>Chen, Alice Y.A.</creatorcontrib><creatorcontrib>Taylor, David S.</creatorcontrib><creatorcontrib>Ying, Xiaohong</creatorcontrib><creatorcontrib>Onorato, Joelle M.</creatorcontrib><creatorcontrib>Galella, Michael</creatorcontrib><creatorcontrib>Shen, Hong</creatorcontrib><creatorcontrib>Huang, Christine S.</creatorcontrib><creatorcontrib>Toussaint, Nathalie</creatorcontrib><creatorcontrib>Li, Yi-Xin</creatorcontrib><creatorcontrib>Abell, Lynn</creatorcontrib><creatorcontrib>Adam, Leonard P.</creatorcontrib><creatorcontrib>Gordon, David</creatorcontrib><creatorcontrib>Wexler, Ruth R.</creatorcontrib><creatorcontrib>Finlay, Heather J.</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>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hu, Carol H.</au><au>Wang, Tammy C.</au><au>Qiao, Jennifer X.</au><au>Haque, Lauren</au><au>Chen, Alice Y.A.</au><au>Taylor, David S.</au><au>Ying, Xiaohong</au><au>Onorato, Joelle M.</au><au>Galella, Michael</au><au>Shen, Hong</au><au>Huang, Christine S.</au><au>Toussaint, Nathalie</au><au>Li, Yi-Xin</au><au>Abell, Lynn</au><au>Adam, Leonard P.</au><au>Gordon, David</au><au>Wexler, Ruth R.</au><au>Finlay, Heather J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery and synthesis of tetrahydropyrimidinedione-4-carboxamides as endothelial lipase inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2018-12-15</date><risdate>2018</risdate><volume>28</volume><issue>23-24</issue><spage>3721</spage><epage>3725</epage><pages>3721-3725</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
•A series of tetrahydropyrimidinedione EL inhibitors was identified.•New compounds showed measurable EL inhibition in human serum.•Optimization led to 4a with micromolar human serum potency and 3g with acceptable mouse PK.
Endothelial lipase (EL) inhibitors have been shown to elevate HDL-C levels in pre-clinical murine models and have potential benefit in prevention and treatment of cardiovascular diseases. Modification of the 1-ethyl-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one (DHP) lead, 1, led to the discovery of a series of potent tetrahydropyrimidinedione (THP) EL inhibitors. Synthesis and SAR studies including modification of the amide group, together with changes on the pyrimidinone core led to a series of arylcycloalkyl, indanyl, and tetralinyl substituted 5-amino or 5-hydroxypyrimidinedione-4-carboxamides. Several compounds were advanced to PK evaluation. Among them, compound 4a was one of the most potent with measurable ELHDL hSerum potency and compound 3g demonstrated the best overall pharmacokinetic parameters.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>30348490</pmid><doi>10.1016/j.bmcl.2018.10.022</doi><tpages>5</tpages></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2018-12, Vol.28 (23-24), p.3721-3725 |
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| subjects | Animals Atherosclerosis Cholesterol, HDL - blood Cholesterol, HDL - metabolism Endothelial lipase (EL) inhibitors Enzyme Inhibitors - blood Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology High density lipoprotein cholesterol (HDL-C) Humans Lipase - antagonists & inhibitors Lipase - blood Lipase - metabolism Mice Models, Molecular Pyrimidinones - blood Pyrimidinones - chemical synthesis Pyrimidinones - chemistry Pyrimidinones - pharmacology Structure-Activity Relationship Tetrahydropyrimidinedione (THP) |
| title | Discovery and synthesis of tetrahydropyrimidinedione-4-carboxamides as endothelial lipase inhibitors |
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