Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Crystallography, X-Ray
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Cyclobutanes / chemical synthesis*
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Cyclobutanes / chemistry
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Cyclobutanes / pharmacology
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Genes, Reporter
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Glucagon-Like Peptide-1 Receptor
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HEK293 Cells
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Humans
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Hypoglycemic Agents / chemical synthesis*
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Hypoglycemic Agents / chemistry
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Hypoglycemic Agents / pharmacology
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Magnetic Resonance Spectroscopy
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Obese
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Molecular Structure
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Photochemical Processes
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Phthalic Acids / chemical synthesis*
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Phthalic Acids / chemistry
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Phthalic Acids / pharmacology
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Radioligand Assay
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Rats
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Receptors, Glucagon / agonists*
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Response Elements
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Stereoisomerism
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Structure-Activity Relationship
Substances
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1,3-bis(4-isobutyramidobenzamido)-2,4-bis(3-methoxy-4-(thiophene-2-carbonyloxy)phenyl)cyclobutane-1,3-dicarboxylic acid
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Cyclobutanes
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GLP1R protein, human
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Glp1r protein, mouse
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Glp1r protein, rat
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Glucagon-Like Peptide-1 Receptor
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Hypoglycemic Agents
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Phthalic Acids
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Receptors, Glucagon