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

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...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2012-01, Vol.55 (1), p.250-267
Main Authors: Liu, Qing, Li, Na, Yuan, Yunyun, Lu, Huili, Wu, Xiaoyan, Zhou, Caihong, He, Min, Su, Haoran, Zhang, Meng, Wang, Jia, Wang, Bao, Wang, You, Ma, Dawei, Ye, Yang, Weiss, Hans-Christoph, Gesing, Ernst R. F, Liao, Jiayu, Wang, Ming-Wei
Format: Article
Language:English
Subjects:
Animals
Crystallography, X-Ray
Cyclobutanes - chemical synthesis
Cyclobutanes - chemistry
Cyclobutanes - pharmacology
Genes, Reporter
Glucagon-Like Peptide-1 Receptor
HEK293 Cells
Humans
Hypoglycemic Agents - chemical synthesis
Hypoglycemic Agents - chemistry
Hypoglycemic Agents - pharmacology
Magnetic Resonance Spectroscopy
Male
Mice
Mice, Inbred C57BL
Mice, Obese
Molecular Structure
Photochemical Processes
Phthalic Acids - chemical synthesis
Phthalic Acids - chemistry
Phthalic Acids - pharmacology
Radioligand Assay
Rats
Receptors, Glucagon - agonists
Response Elements
Stereoisomerism
Structure-Activity Relationship
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm201150j