D-Tyrosine as a chiral precusor to potent inhibitors of human nonpancreatic secretory phospholipase A2 (IIa) with antiinflammatory activity

Chembiochem. 2003 Mar 3;4(2-3):181-5. doi: 10.1002/cbic.200390029.

Abstract

Few reported inhibitors of secretory phospholipase A(2) enzymes truly inhibit the IIa human isoform (hnpsPLA(2)-IIa) noncovalently at submicromolar concentrations. Herein, the simple chiral precursor D-tyrosine was derivatised to give a series of potent new inhibitors of hnpsPLA(2)-IIa. A 2.2-A crystal structure shows an inhibitor bound in the active site of the enzyme, chelated to a Ca(2+) ion through carboxylate and amide oxygen atoms, H-bonded through an amide NH group to His48, with multiple hydrophobic contacts and a T-shaped aromatic-group-His6 interaction. Antiinflammatory activity is also demonstrated for two compounds administered orally to rats.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Experimental / drug therapy
  • Arthritis, Experimental / prevention & control
  • Crystallography, X-Ray
  • Disease Models, Animal
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Inflammation / chemically induced
  • Inflammation / drug therapy*
  • Inflammation / prevention & control
  • Phospholipases A / antagonists & inhibitors*
  • Phospholipases A / pharmacology*
  • Phospholipases A2
  • Rats
  • Rats, Wistar
  • Structure-Activity Relationship
  • Tyrosine / chemical synthesis*
  • Tyrosine / pharmacokinetics

Substances

  • Enzyme Inhibitors
  • Tyrosine
  • Phospholipases A
  • Phospholipases A2