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

被引:47
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
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
收藏
页码:250 / 267
页数:18
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