Structure-based optimisation of orally active & reversible MetAP-2 inhibitors maintaining a tight 'molecular budget'

Bioorg Med Chem Lett. 2020 Nov 1;30(21):127533. doi: 10.1016/j.bmcl.2020.127533. Epub 2020 Sep 10.

Abstract

Structure-based led optimisation of orally active reversible Methionine Aminopeptidase-2 (MetAP-2) inhibitors utilising a 'molecular budget' medicinal chemistry strategy is described. The key physicochemical parameters of target molecules (cLogP, molecular size and H-bond donor count) were monitored through straightforward and intuitive use of atom count and distribution. The balance between structure-based design and an awareness of the physicochemical properties of the compounds synthesised enabled the rapid identification of a potent molecule with good oral pharmacokinetic (PK) characteristics by making fewer, higher quality compounds. The resulting candidate quality molecule was validated in a mechanistic cellular assay and a rodent secondary immunisation model.

Keywords: Indole carboxamide; MetAP-2; Methionine aminopeptidase-2; Molecular budget; Structure-based drug design.

MeSH terms

  • Chemistry, Pharmaceutical
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Indoles / chemical synthesis
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Methionyl Aminopeptidases / antagonists & inhibitors*
  • Methionyl Aminopeptidases / metabolism
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Indoles
  • indole
  • METAP2 protein, human
  • Methionyl Aminopeptidases