A new class of prolylcarboxypeptidase inhibitors, part 2: the aminocyclopentanes

Bioorg Med Chem Lett. 2012 Apr 15;22(8):2818-22. doi: 10.1016/j.bmcl.2012.02.077. Epub 2012 Mar 1.

Abstract

A series of potent inhibitors of prolylcarboxypeptidase (PrCP) was developed by modifying a lead structure that was discovered by high-throughput screening. The tert-butyl pyrrolidine was replaced by an aminocyclopentane to reduce the metabolic liabilities of the original lead. The compounds demonstrated sub-nanomolar in vitro IC(50) values, minimal activity shifts in pure plasma and improved pharmacokinetics. Complete ex vivo plasma target engagement was achieved with low brain exposure at the 20 h time point following p.o. dosing in a mouse. The results indicate that the aminocyclopentanes are useful tools for studying the therapeutic potential of peripheral (non-CNS) PrCP inhibition.

MeSH terms

  • Amines / chemical synthesis
  • Amines / chemistry
  • Amines / pharmacology*
  • Animals
  • Carboxypeptidases / antagonists & inhibitors*
  • Cyclization
  • Cyclopentanes / chemical synthesis
  • Cyclopentanes / chemistry
  • Cyclopentanes / pharmacology*
  • Drug Discovery*
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors* / chemistry
  • Enzyme Inhibitors* / pharmacology
  • Inhibitory Concentration 50
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Structure
  • Obesity / drug therapy

Substances

  • Amines
  • Cyclopentanes
  • Enzyme Inhibitors
  • Carboxypeptidases
  • lysosomal Pro-X carboxypeptidase