A new class of prolylcarboxypeptidase inhibitors, part 1: discovery and evaluation

Bioorg Med Chem Lett. 2012 Apr 15;22(8):2811-7. doi: 10.1016/j.bmcl.2012.02.075. Epub 2012 Mar 1.

Abstract

A new structural class of potent prolylcarboxypeptidase (PrCP) inhibitors was discovered by high-throughput screening. The series possesses a tractable SAR profile with sub-nanomolar in vitro IC(50) values. Compared to prior inhibitors, the new series demonstrated minimal activity shifts in pure plasma and complete ex vivo plasma target engagement in mouse plasma at the 20 h post-dose time point (po). In addition, the in vivo level of CNS and non-CNS drug exposure was measured.

MeSH terms

  • Animals
  • Butanols / chemical synthesis
  • Butanols / chemistry
  • Butanols / pharmacology
  • Carboxypeptidases / antagonists & inhibitors*
  • 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
  • Pyrrolidines / chemical synthesis
  • Pyrrolidines / chemistry
  • Pyrrolidines / pharmacology

Substances

  • Butanols
  • Enzyme Inhibitors
  • Pyrrolidines
  • Carboxypeptidases
  • lysosomal Pro-X carboxypeptidase
  • pyrrolidine