Discovery of aminoheterocycles as potent and brain penetrant prolylcarboxypeptidase inhibitors

Bioorg Med Chem Lett. 2012 Feb 15;22(4):1727-30. doi: 10.1016/j.bmcl.2011.12.098. Epub 2012 Jan 8.

Abstract

Efforts were dedicated to develop potent and brain penetrant prolylcarboxypeptidase (PrCP) inhibitors by replacing the amide group of original leads 1 and 2 with heterocycles. Aminopyrimidines including compound 32a were identified to display good PrCP inhibitory activity (32a, IC(50)=43 nM) and impressive ability to penetrate brain in mice (brain/plasma ratio: 1.4).

MeSH terms

  • Amides / chemistry
  • Amines / chemical synthesis*
  • Amines / chemistry
  • Amines / pharmacology
  • Animals
  • Brain / drug effects*
  • Brain / enzymology
  • Carboxypeptidases / antagonists & inhibitors*
  • Drug Discovery*
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors* / chemical synthesis
  • Enzyme Inhibitors* / pharmacology
  • Heterocyclic Compounds / chemical synthesis*
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / pharmacology*
  • Inhibitory Concentration 50
  • Mice
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Amides
  • Amines
  • Enzyme Inhibitors
  • Heterocyclic Compounds
  • Carboxypeptidases
  • lysosomal Pro-X carboxypeptidase