2-Oxoamide inhibitors of cytosolic group IVA phospholipase A2 with reduced lipophilicity

被引：5

作者：

Antonopoulou, Georgia ^{[1
,4
]}

Magrioti, Victoria ^{[1
]}

Kokotou, Maroula G. ^{[1
]}

Nikolaou, Aikaterini ^{[1
]}

Barbayianni, Efrosini ^{[1
]}

Mouchlis, Varnavas D. ^{[2
,3
]}

Dennis, Edward A. ^{[2
,3
]}

Kokotos, George ^{[1
]}

机构：

[1] Univ Athens, Dept Chem, Athens 15771, Greece

[2] Univ Calif San Diego, Sch Med, Dept Chem & Biochem, MC 0601, La Jolla, CA 92093 USA

[3] Univ Calif San Diego, Sch Med, Dept Pharmacol, MC 0601, La Jolla, CA 92093 USA

[4] Natl Hellen Res Fdn, Inst Biol Med Chem & Biotechnol, Athens, Greece

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2016年 / 24卷 / 19期

关键词：

GIVA cPLA(2); Inhibitors; Lipophilicity; 2-Oxoamides; Phospholipase A(2); IN-VITRO; PYRROLIDINE INHIBITORS; METABOLIC STABILITY; BIOLOGICAL-ACTIVITY; AMINO-ACIDS; A(2)ALPHA; DISCOVERY; POTENT; SERIES; 1-INDOL-1-YL-PROPAN-2-ONES;

D O I：

10.1016/j.bmc.2016.07.057

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Cytosolic GIVA phospholipase A(2) (GIVA cPLA(2)) initiates the eicosanoid pathway of inflammation and thus inhibitors of this enzyme constitute novel potential agents for the treatment of inflammatory diseases. Traditionally, GIVA cPLA(2) inhibitors have suffered systemically from high lipophilicity. We have developed a variety of long chain 2-oxoamides as inhibitors of GIVA PLA(2). Among them, AX048 was found to produce a potent analgesic effect. We have now reduced the lipophilicity of AX048 by replacing the long aliphatic chain with a chain containing an ether linked aromatic ring with in vitro inhibitory activities similar to AX048. (C) 2016 Elsevier Ltd. All rights reserved.

引用

页码：4544 / 4554

页数：11

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