Discovery of benzimidazole pyrrolidinyl amides as prolylcarboxypeptidase inhibitors

Bioorg Med Chem Lett. 2011 Mar 1;21(5):1299-305. doi: 10.1016/j.bmcl.2011.01.090. Epub 2011 Jan 26.

Abstract

A series of benzimidazole pyrrolidinyl amides containing a piperidinyl group were discovered as novel prolylcarboxypeptidase (PrCP) inhibitors. Low-nanomolar IC(50)'s were achieved for several analogs, of which compound 9b displayed modest ex vivo target engagement in eDIO mouse plasma. Compound 9b was also studied in vivo for its effect on weight loss and food intake in an eDIO mouse model and the results will be discussed.

MeSH terms

  • Amides* / chemistry
  • Amides* / pharmacology
  • Animals
  • Benzimidazoles* / chemistry
  • Benzimidazoles* / pharmacology
  • Carboxypeptidases / antagonists & inhibitors*
  • Disease Models, Animal
  • Drug Discovery*
  • Enzyme Inhibitors* / chemistry
  • Enzyme Inhibitors* / pharmacology
  • Humans
  • Inhibitory Concentration 50
  • Mice
  • Molecular Structure
  • Pyrrolidines* / chemistry
  • Pyrrolidines* / pharmacology
  • Structure-Activity Relationship

Substances

  • Amides
  • Benzimidazoles
  • Enzyme Inhibitors
  • Pyrrolidines
  • Carboxypeptidases
  • lysosomal Pro-X carboxypeptidase