Benzothiazole-based compounds as potent endothelial lipase inhibitors

Bioorg Med Chem Lett. 2019 Oct 15;29(20):126673. doi: 10.1016/j.bmcl.2019.126673. Epub 2019 Sep 6.

Abstract

A series of benzothiazoles with a cyano group was synthesized and evaluated as endothelial lipase (EL) inhibitors for the potential treatment of cardiovascular diseases. Efforts to reduce molecular weight and polarity in the series led to improved physicochemical properties of these compounds, as well as selectivity for EL over hepatic lipase (HL). As a benchmark compound, 8i demonstrated potent EL activity, an acceptable absorption, distribution, metabolism and elimination (ADME) profile and pharmacokinetic (PK) exposure which allowed further evaluation in preclinical animal efficacy studies.

Keywords: Benzothiazole; Cardiovascular diseases; Endothelial lipase; High density lipoprotein; Structure-activity relationship.

MeSH terms

  • Animals
  • Benzothiazoles / chemistry*
  • Benzothiazoles / pharmacology
  • Cardiovascular Diseases / drug therapy*
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation / drug effects
  • Humans
  • Lipase / antagonists & inhibitors*
  • Lipase / genetics
  • Lipoproteins, HDL / metabolism
  • Lipoproteins, LDL / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Benzothiazoles
  • Enzyme Inhibitors
  • Lipoproteins, HDL
  • Lipoproteins, LDL
  • LIPG protein, human
  • Lipase