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.
Karl A Hansford  1 ,  Robert C Reid ,  Chris I Clark ,  Joel D A Tyndall ,  Michael W Whitehouse ,  Tom Guthrie ,  Ross P McGeary ,  Karl Schafer ,  Jennifer L Martin ,  David P Fairlie
Affiliations
  • 1. Centre for Drug Design and Development, Institute for Molecular Bioscience, University of Queensland Brisbane, Australia.
PMID: 12616631 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.

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