Large dimeric ligands with favorable pharmacokinetic properties and peroxisome proliferator-activated receptor agonist activity in vitro and in vivo

被引：32

作者：

Sauerberg, P ^{[1
]}

Bury, PS ^{[1
]}

Mogensen, JP ^{[1
]}

Deussen, HJ ^{[1
]}

Pettersson, I ^{[1
]}

Fleckner, J ^{[1
]}

Nehlin, J ^{[1
]}

Frederiksen, KS ^{[1
]}

Albrektsen, T ^{[1
]}

Din, NN ^{[1
]}

Svensson, LA ^{[1
]}

Ynddal, L ^{[1
]}

Wulff, EM ^{[1
]}

Jeppesen, L ^{[1
]}

机构：

[1] Novo Nordisk AS, Sauerberg, DK-2760 Malov, Denmark

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2003年 / 46卷 / 23期

关键词：

D O I：

10.1021/jm0309046

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Two potent nonselective, but PPARalpha-preferring, PPAR agonists 5 and 6 were designed and synthesized in high yields. The concept of dimeric ligands in transcription factors was investigated by synthesizing and testing the corresponding dimers 7, 8a, and 8b in PPAR transactivation assays. The three dimeric ligands all showed agonist activity on all three PPAR receptor subtypes, but with different profiles compared to the monomers 5 and 6. Despite breaking all the "rule of five" criteria, the dimers had excellent oral bioavailability and pharmacokinetic properties, resulting in good in vivo efficacy in db/db mice. X-ray crystal structure and modeling experiments suggested that the dimers interacted with the AF-2 helix as well as with amino acid residues in the lipophilic pocket close to the receptor surface.

引用

页码：4883 / 4894

页数：12

共 41 条

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