Synthesis of proline analogues as potent and selective cathepsin S inhibitors

Bioorg Med Chem Lett. 2013 Jun 1;23(11):3140-4. doi: 10.1016/j.bmcl.2013.04.023. Epub 2013 Apr 16.

Abstract

Cathepsin S is a potential target of autoimmune disease. A series of proline derived compounds were synthesized and evaluated as cathepsin S inhibitors. We discovered potent cathepsin S inhibitors through structure-activity relationship studies of proline analogues. In particular, compound 19-(S) showed promising in vitro/vivo pharmacological activities and properties as a selective cathepsin S inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis / chemically induced
  • Arthritis / drug therapy
  • Benzoxazoles / chemical synthesis*
  • Benzoxazoles / pharmacokinetics
  • Benzoxazoles / therapeutic use
  • Cathepsin B / antagonists & inhibitors
  • Cathepsin B / metabolism
  • Cathepsin K / antagonists & inhibitors
  • Cathepsin K / metabolism
  • Cathepsins / antagonists & inhibitors*
  • Cathepsins / metabolism
  • Collagen / toxicity
  • Disease Models, Animal
  • Dogs
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / therapeutic use
  • Half-Life
  • Humans
  • Mice
  • Mice, Inbred ICR
  • Microsomes / metabolism
  • Proline / analogs & derivatives*
  • Proline / chemical synthesis
  • Proline / pharmacokinetics
  • Proline / therapeutic use
  • Protein Binding
  • Rats
  • Rats, Sprague-Dawley
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Benzoxazoles
  • Enzyme Inhibitors
  • Collagen
  • Proline
  • Cathepsins
  • Cathepsin B
  • cathepsin S
  • Cathepsin K