Cyclobutane Derivatives As Novel Nonpeptidic Small Molecule Agonists of Glucagon-Like Peptide-1 Receptor
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- 作者：Qing Liu ; Na Li ; Yunyun Yuan ; Huili Lu ; Xiaoyan Wu ; Caihong Zhou ; Min He ; Haoran Su ; Meng Zhang ; Jia Wang ; Bao Wang ; You Wang ; Dawei Ma ; Yang Ye ; Hans-Christoph Weiss ; Ernst R. F. Gesing ; Jiayu Liao ; Ming-Wei Wang
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：January 12, 2012
- 年：2012
- 卷：55
- 期：1
- 页码：250-267
- 全文大小：649K
- 年卷期：v.55,no.1(January 12, 2012)
- ISSN：1520-4804
文摘
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.