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. Epub 2018 Oct 15.

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).

MeSH terms

  • Animals
  • Cholesterol, HDL / blood
  • Cholesterol, HDL / metabolism
  • Enzyme Inhibitors / blood
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Lipase / antagonists & inhibitors*
  • Lipase / blood
  • Lipase / metabolism
  • Mice
  • Models, Molecular
  • Pyrimidinones / blood
  • Pyrimidinones / chemical synthesis
  • Pyrimidinones / chemistry*
  • Pyrimidinones / pharmacology*
  • Structure-Activity Relationship

Substances

  • Cholesterol, HDL
  • Enzyme Inhibitors
  • Pyrimidinones
  • tetrahydropyrimidinone
  • LIPG protein, human
  • Lipase