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 <b>3</b>, was identified using receptor binding and multiple response element/cAMP response element (MRE/CRE)-driven reporter gene assays. The structures of <b>3</b> 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 <b>3</b> with different substitution groups at the west and east ends. Among these analogues, compound <b>16</b> was found to be 4- to 5-fold more potent than <b>3</b> both in vitro and in vivo