The first potent inhibitor of mammalian group X secreted phospholipase A2: elucidation of sites for enhanced binding

J Med Chem. 2006 May 18;49(10):2858-60. doi: 10.1021/jm060136t.

Abstract

Using the X-ray structure of human group X secreted phospholipase A(2) (hGX), we carried out structure-based design of indole-based inhibitors and prepared the compounds using a new synthetic route. The most potent compound inhibited hGX and the mouse orthologue with an IC(50) of 75 nM. This compound is the most potent hGX inhibitor reported to date and was also found to inhibit a subset of the other mouse and human sPLA(2)s.

MeSH terms

  • Animals
  • Binding Sites
  • Crystallography, X-Ray
  • Group X Phospholipases A2
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / pharmacology
  • Mice
  • Models, Molecular
  • Phospholipases A / antagonists & inhibitors*
  • Phospholipases A / chemistry*
  • Phospholipases A2
  • Structure-Activity Relationship

Substances

  • Indoles
  • Phospholipases A
  • Group X Phospholipases A2
  • PLA2G10 protein, human
  • Phospholipases A2
  • Pla2g10 protein, mouse