Azepanone-based inhibitors of human cathepsin S: optimization of selectivity via the P2 substituent

Bioorg Med Chem Lett. 2011 Aug 1;21(15):4409-15. doi: 10.1016/j.bmcl.2011.06.045. Epub 2011 Jun 17.

Abstract

A series of azepanone inhibitors of cathepsin S is described. Selectivity over both cathepsin K and cathepsin L was achieved by varying the P2 substituent. Ultimately, a balanced potency and selectivity profile was achieved in compound 39 possessing a 1-methylcyclohexyl alanine at P2 and nicotinamide as the P' substituent. The cellular potency of selected analogs is also described.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine / chemistry
  • Azepines / chemical synthesis
  • Azepines / chemistry*
  • Azepines / pharmacology
  • Binding Sites
  • Cathepsin K / antagonists & inhibitors
  • Cathepsin K / metabolism
  • Cathepsin L / antagonists & inhibitors
  • Cathepsin L / metabolism
  • Cathepsins / antagonists & inhibitors*
  • Cathepsins / metabolism
  • Computer Simulation
  • Humans
  • Niacinamide / analogs & derivatives*
  • Niacinamide / chemical synthesis
  • Niacinamide / chemistry
  • Niacinamide / pharmacology
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Azepines
  • Protease Inhibitors
  • Niacinamide
  • Cathepsins
  • Cathepsin L
  • cathepsin S
  • Cathepsin K
  • Alanine