Discovery of potent, reversible MetAP2 inhibitors via fragment based drug discovery and structure based drug design-Part 1

Bioorg Med Chem Lett. 2016 Jun 15;26(12):2774-2778. doi: 10.1016/j.bmcl.2016.04.073. Epub 2016 Apr 25.

Abstract

Methionine aminopeptidase 2 (MetAP2) is an enzyme that cleaves an N-terminal methionine residue from a number of newly synthesized proteins. Pre-clinical and clinical studies suggest that MetAP2 inhibitors could be used as a novel treatment for obesity. Herein we describe our use of fragment screening methods and structural biology to quickly identify and elaborate an indazole fragment into a series of reversible MetAP2 inhibitors with <10nM potency, excellent selectivity, and favorable in vitro safety profiles.

Keywords: FBDD; Fragment-based drug discovery; Indazole; MetAP2; Metalloprotease; Methionine aminopeptidase 2.

MeSH terms

  • Administration, Oral
  • Aminopeptidases / antagonists & inhibitors*
  • Aminopeptidases / metabolism
  • Animals
  • Body Weight / drug effects*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Glycoproteins / antagonists & inhibitors*
  • Glycoproteins / metabolism
  • Humans
  • Indazoles / chemical synthesis
  • Indazoles / chemistry
  • Indazoles / pharmacology*
  • Methionyl Aminopeptidases
  • Mice
  • Mice, Obese
  • Models, Molecular
  • Molecular Structure
  • Obesity / drug therapy*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Glycoproteins
  • Indazoles
  • Aminopeptidases
  • METAP2 protein, human
  • Methionyl Aminopeptidases