Nonpeptide inhibitors of cathepsin G: Optimization of a novel β-ketophosphonic acid lead by structure-based drug design

Academic Article


  • The serine protease cathepsin G (EC; Cat G), which is stored in the azurophilic granules of neutrophils (polymorphonuclear leukocytes) and released on degranulation, has been implicated in various pathological conditions associated with inflammation. By employing high-throughput screening, we identified β-ketophosphonic acid 1 as a moderate inhibitor of Cat G (IC50 = 4.1 μM). We were fortunate to obtain a cocrystal of 1 with Cat G and solve its structure by X-ray crystallography (3.5 Å). Structural details from the X-ray analysis of 1·Cat G served as a platform for optimization of this lead compound by structure-based drug design. With the aid of molecular modeling, substituents were attached to the 3-position of the 2-naphthyl ring of 1, which occupies the S1 pocket of Cat G, to provide an extension into the hydrophobic S3 region. Thus, we arrived at analogue 7 with an 80-fold potency improvement over 1 (IC50 = 53 nM). From these results, it is evident that the β-ketophosphonic acid unit can form the basis for a novel class of serine protease inhibitors. Copyright © 2002 American Chemical Society.
  • Digital Object Identifier (doi)

    Pubmed Id

  • 1658954
  • Author List

  • Greco MN; Hawkins MJ; Powell ET; Almond HR; Corcoran TW; De Garavilla L; Kauffman JA; Recacha R; Chattopadhyay D; Andrade-Gordon P
  • Start Page

  • 3810
  • End Page

  • 3811
  • Volume

  • 124
  • Issue

  • 15