Discovery of potent, reversible MetAP2 inhibitors via fragment based drug discovery and structure based drug design-Part 2

Bioorg Med Chem Lett. 2016 Jun 15;26(12):2779-2783. doi: 10.1016/j.bmcl.2016.04.072. Epub 2016 Apr 25.


Methionine aminopeptidase-2 (MetAP2) is an enzyme that cleaves an N-terminal methionine residue from a number of newly synthesized proteins. This step is required before they will fold or function correctly. Pre-clinical and clinical studies with a MetAP2 inhibitor suggest that they could be used as a novel treatment for obesity. Herein we describe the discovery of a series of pyrazolo[4,3-b]indoles as reversible MetAP2 inhibitors. A fragment-based drug discovery (FBDD) approach was used, beginning with the screening of fragment libraries to generate hits with high ligand-efficiency (LE). An indazole core was selected for further elaboration, guided by structural information. SAR from the indazole series led to the design of a pyrazolo[4,3-b]indole core and accelerated knowledge-based fragment growth resulted in potent and efficient MetAP2 inhibitors, which have shown robust and sustainable body weight loss in DIO mice when dosed orally.

Keywords: FBDD; Fragment-based drug discovery; MetAP2; Metalloprotease; Methionine aminopeptidase-2; Pyrazolo[4,3-b]indoles; SBDD; Structure-based drug design.

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
  • Indoles / administration & dosage
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Methionyl Aminopeptidases
  • Mice
  • Mice, Obese
  • Models, Molecular
  • Molecular Structure
  • Obesity / drug therapy*
  • Pyrazoles / administration & dosage
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Structure-Activity Relationship


  • Enzyme Inhibitors
  • Glycoproteins
  • Indoles
  • Pyrazoles
  • Aminopeptidases
  • METAP2 protein, human
  • Methionyl Aminopeptidases