Cyclobutane Derivatives As Novel Nonpeptidic Small Molecule Agonists of Glucagon-Like Peptide-1 Receptor

被引：49

作者：

Liu, Qing ^{[1
]}

Li, Na ^{[1
]}

Yuan, Yunyun ^{[1
]}

Lu, Huili ^{[1
]}

Wu, Xiaoyan ^{[1
]}

Zhou, Caihong ^{[1
,2
]}

He, Min ^{[1
,2
]}

Su, Haoran ^{[1
]}

Zhang, Meng ^{[1
]}

Wang, Jia ^{[1
]}

Wang, Bao ^{[3
]}

Wang, You ^{[3
]}

Ma, Dawei ^{[3
]}

Ye, Yang ^{[2
]}

Weiss, Hans-Christoph ^{[4
]}

Gesing, Ernst R. F. ^{[5
]}

Liao, Jiayu ^{[1
]}

Wang, Ming-Wei ^{[1
,2
]}

机构：

[1] Natl Ctr Drug Screening, Shanghai 201203, Peoples R China

[2] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China

[3] Chinese Acad Sci, Shanghai Inst Organ Chem, Shanghai 200032, Peoples R China

[4] Currenta GmbH & Co OHG, D-20833 Leverkusen, Amtsgericht Kol, Germany

[5] Bayer CropSci Aktiengesell, D-40789 Monheim, Germany

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 01期

关键词：

ACID; PHOTODIMERIZATION; EFFICACY; THERAPY;

D O I：

10.1021/jm201150j

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel cyclobutane class of nonpeptidic glucagon-like peptide-1 (GLP-1) receptor agonists, exemplified by 3, was identified using receptor binding and multiple response element/cAMP response element (MRE/CRE)-driven reporter gene assays. The structures of 3 and its three isomers were elucidated by NMR, HRESIMS, and X-ray crystallography. A series of structural modifications were also made based on the core structure of 3 with different substitution groups at the west and east ends. Among these analogues, compound 16 was found to be 4- to 5-fold more potent than 3 both in vitro and in vivo.

引用

页码：250 / 267

页数：18

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