Synthesis, Biological Evaluation and Molecular Modeling of GW 501516 Analogues

被引：5

作者：

Ciocoiu, Calin C. ^{[1
]}

Ravna, Aina W. ^{[2
]}

Sylte, Ingebrigt ^{[2
]}

Hansen, Trond Vidar ^{[1
]}

机构：

[1] Univ Oslo, Sch Pharm, Dept Pharmaceut Chem, N-0316 Oslo, Norway

[2] Univ Tromso, Dept Med Biol, Fac Hlth Sci, Tromso, Norway

来源：

ARCHIV DER PHARMAZIE | 2010年 / 343卷 / 11-12期

关键词：

GW; 501516; Agonists; Multi well assay; Molecular modeling; PPAR alpha; PPAR delta; PHENYLPROPANOIC ACID-DERIVATIVES; PPAR-DELTA AGONIST; PEROXISOME-PROLIFERATOR; DUAL AGONISTS; DESIGN; POTENT; IDENTIFICATION; METABOLISM; ACTIVATION; SERIES;

D O I：

10.1002/ardp.201000189

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Eleven analogues of GW 501516 (1) were prepared and subjected to biological testing in a semi-high throughput human skeletal muscle cell assay. The assay testing indicated that all analogues elicited oxidation of oleic acid. Among the most potent agonists, 2e (2-{2-ethyl-4-[(4-methyl-2-(4-trifluoromethylphenyl) thiazol-5-yl)methylthio]phenoxy}-2-methylpropanoic acid), was also subjected to a luciferase-based transfection assay, which showed that this compound is a potent agonist against PPAR delta and a moderate agonist against PPAR alpha. Docking of compound 2e into PPAR delta revealed that it occupied the agonist binding site and exhibited key hydrogen bonding interactions with His323, His449, and Tyr473.

引用

页码：612 / 624

页数：13

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