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.