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.
Hansford
Karl A
KA
Centre for Drug Design and Development, Institute for Molecular Bioscience, University of Queensland Brisbane, Australia.
Reid
Robert C
RC
Clark
Chris I
CI
Tyndall
Joel D A
JD
Whitehouse
Michael W
MW
Guthrie
Tom
T
McGeary
Ross P
RP
Schafer
Karl
K
Martin
Jennifer L
JL
Fairlie
David P
DP
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000517:prevention & control; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D054467:Phospholipases A2; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000138:chemical synthesis* / Q000493:pharmacokinetics
D004791:Enzyme Inhibitors; D014443:Tyrosine; D010741:Phospholipases A; D054467:Phospholipases A2