Discovery of BI 99179, a potent and selective inhibitor of type I fatty acid synthase with central exposure

Bioorg Med Chem Lett. 2011 Oct 1;21(19):5924-7. doi: 10.1016/j.bmcl.2011.07.083. Epub 2011 Aug 9.

Abstract

Based on a high-throughput screen, cyclopentanecarboxanilides were identified as a new chemotype of non-covalent inhibitors of type I fatty acid synthase (FAS). Starting from initial hits we aimed at generating a tool compound suitable for the in vivo validation of FAS as a therapeutic target. Optimisation yielded BI 99179 which is characterised by high potency, remarkably high selectivity and significant exposure (both peripheral and central) upon oral administration in rats.

MeSH terms

  • Administration, Oral
  • Animals
  • Benzoxazoles / chemical synthesis*
  • Benzoxazoles / pharmacokinetics
  • Benzoxazoles / pharmacology*
  • Benzoxazoles / toxicity
  • Caco-2 Cells
  • Cell Line
  • Cytochrome P-450 Enzyme Inhibitors
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Fatty Acid Synthases / antagonists & inhibitors*
  • High-Throughput Screening Assays
  • Humans
  • Hypothalamus
  • Inhibitory Concentration 50
  • Injections, Intravenous
  • Mice
  • Microsomes, Liver / metabolism
  • Molecular Conformation
  • Molecular Targeted Therapy
  • Permeability
  • Proline / analogs & derivatives*
  • Proline / chemical synthesis
  • Proline / pharmacokinetics
  • Proline / pharmacology
  • Proline / toxicity
  • Rats
  • Stereoisomerism
  • Structure-Activity Relationship
  • Substrate Specificity

Substances

  • BI 99179
  • Benzoxazoles
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Proline
  • Fatty Acid Synthases