2. Academic Validation
  3. Discovery and synthesis of tetrahydropyrimidinedione-4-carboxamides as endothelial lipase inhibitors

Discovery and synthesis of tetrahydropyrimidinedione-4-carboxamides as endothelial lipase inhibitors

  • Bioorg Med Chem Lett. 2018 Dec 15;28(23-24):3721-3725. doi: 10.1016/j.bmcl.2018.10.022.
Carol H Hu 1,  Tammy C Wang 2,  Jennifer X Qiao 3,  Lauren Haque 3,  Alice Y A Chen 3,  David S Taylor 3,  Xiaohong Ying 3,  Joelle M Onorato 3,  Michael Galella 3,  Hong Shen 3,  Christine S Huang 3,  Nathalie Toussaint 3,  Yi-Xin Li 3,  Lynn Abell 3,  Leonard P Adam 3,  David Gordon 3,  Ruth R Wexler 3,  Heather J Finlay 3
Affiliations

Affiliations

  • 1 Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, United States. Electronic address: Carol.Hu@bms.com.
  • 2 Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, United States. Electronic address: Tammy.Wang@bms.com.
  • 3 Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, United States.
PMID: 30348490 DOI: 10.1016/j.bmcl.2018.10.022
Abstract

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.

Keywords

Atherosclerosis; Endothelial lipase (EL) inhibitors; High density lipoprotein cholesterol (HDL-C); Tetrahydropyrimidinedione (THP).

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