title: D-Tyrosine as a chiral precusor to potent inhibitors of human nonpancreatic secretory phospholipase A2 (IIa) with antiinflammatory activity.
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.
authors.affiliation: Centre for Drug Design and Development, Institute for Molecular Bioscience, University of Queensland Brisbane, Australia.
authors.forename: Karl A
authors.initials: KA
authors.lastname: Hansford
authors.forename: Robert C
authors.initials: RC
authors.lastname: Reid
authors.forename: Chris I
authors.initials: CI
authors.lastname: Clark
authors.forename: Joel D A
authors.initials: JD
authors.lastname: Tyndall
authors.forename: Michael W
authors.initials: MW
authors.lastname: Whitehouse
authors.forename: Tom
authors.initials: T
authors.lastname: Guthrie
authors.forename: Ross P
authors.initials: RP
authors.lastname: McGeary
authors.forename: Karl
authors.initials: K
authors.lastname: Schafer
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Martin
authors.forename: David P
authors.initials: DP
authors.lastname: Fairlie
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D014443:Tyrosine; D010741:Phospholipases A; D054467:Phospholipases A2