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.
Mesh Terms:
Animals, Arthritis, Experimental, Crystallography, X-Ray, Disease Models, Animal, Enzyme Inhibitors, Humans, Inflammation, Phospholipases A, Phospholipases A2, Rats, Rats, Wistar, Structure-Activity Relationship, Tyrosine
Chembiochem
Date: Mar. 03, 2003
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