D‐Tyrosine as a Chiral Precusor to Potent Inhibitors of Human Nonpancreatic Secretory Phospholipase A₂ (IIa) with Antiinflammatory Activity

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.