D-Tyrosine as a chiral precusor to potent inhibitors of human nonpancreatic secretory phospholipase A2 (IIa) with antiinflammatory activity

被引：74

作者：

Hansford, KA ^{[1
]}

Reid, RC ^{[1
]}

Clark, CI ^{[1
]}

Tyndall, JDA ^{[1
]}

Whitehouse, MW ^{[1
]}

Guthrie, T ^{[1
]}

McGeary, RP ^{[1
]}

Schafer, K ^{[1
]}

Martin, JL ^{[1
]}

Fairlie, DP ^{[1
]}

机构：

[1] Univ Queensland, Inst Mol Biosci, Ctr Drug Design & Dev, Brisbane, Qld 4072, Australia

来源：

CHEMBIOCHEM | 2003年 / 4卷 / 2-3期

关键词：

enzymes; inflammation; inhibitors; medicinal chemistry; structure-activity relationships;

D O I：

10.1002/cbic.200390029

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 [生物化学与分子生物学]; 081704 [应用化学];

摘要：

Few reported inhibitors of secretory phospholipase A(2) enzymes inhibit the IIa human isoform (hnpsPLA(2)-IIa) noncovalently at submicromolar concentrations. Herein, the simple chiral precursor D-tyrosine was derivastised to give a series of potent new inhibitors of hnpsPLA(2)-IIa. A 2.2-Angstrom crystal structure shows an inhibitor bound in the active site of the enzyme, chelated to a Ca2+ 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.

引用

页码：181 / 185

页数：5

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