Indole inhibitors of human nonpancreatic secretory phospholipase A2. 3. Indole-3-glyoxamides

J Med Chem. 1996 Dec 20;39(26):5159-75. doi: 10.1021/jm960487f.

Abstract

The preceding papers of this series detail the development of functionalized indole-3-acetamides as inhibitors of hnps-PLA2. We describe here the extension of the structure-activity relationship to include a series of indole-3-glyoxamide derivatives. Functionalized indole-3-glyoxamides with an acidic substituent appended to the 4- or 5-position of the indole ring were prepared and tested as inhibitors of hnps-PLA2. It was found that the indole-3-glyoxamides with a 4-oxyacetic acid substituent had optimal inhibitory activity. These inhibitors exhibited an improvement in potency over the best of the indole-3-acetamides, and LY315920 (6m) was selected for evaluation clinically as an hnps-PLA2 inhibitor.

MeSH terms

  • Crystallography, X-Ray
  • Humans
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Phospholipases A / antagonists & inhibitors*
  • Phospholipases A2
  • Structure-Activity Relationship
  • Sulfonylurea Compounds / chemistry*
  • Sulfonylurea Compounds / pharmacology*

Substances

  • Sulfonylurea Compounds
  • glyoxamide
  • Phospholipases A
  • Phospholipases A2