Identification of a novel boronic acid as a potent, selective, and orally active hormone sensitive lipase inhibitor

Bioorg Med Chem. 2016 Aug 15;24(16):3801-7. doi: 10.1016/j.bmc.2016.06.022. Epub 2016 Jun 11.

Abstract

Hormone sensitive lipase (HSL) is an attractive therapeutic target of dyslipidemia. We designed and synthesized several compounds as reversible HSL inhibitors with a focus on hydrophobic interactions, which was thought to be effective upon the HSL inhibitory activity. In these efforts, we identified boronated compound 12 showing a potent HSL inhibitory activity with an IC50 value of 7nM and a high selectivity against cholinesterases. Furthermore, compound 12 is the first boron containing HSL inhibitor that has shown an antilipolytic effect in rats after oral administration at 3mg/kg.

Keywords: Boronic acid; Dyslipidemia; Hormone sensitive lipase (HSL); Lipolysis.

MeSH terms

  • Administration, Oral
  • Animals
  • Boronic Acids / administration & dosage
  • Boronic Acids / pharmacokinetics
  • Boronic Acids / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Male
  • Proton Magnetic Resonance Spectroscopy
  • Rats
  • Rats, Wistar
  • Spectrometry, Mass, Electrospray Ionization
  • Sterol Esterase / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Boronic Acids
  • Enzyme Inhibitors
  • Sterol Esterase