title: Cyclobutane derivatives as novel nonpeptidic small molecule agonists of glucagon-like peptide-1 receptor.
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.
authors: The National Center for Drug Screening, 189 Guo Shou Jing Road, Shanghai 201203, China.
authors: Qing
authors: Q
authors: Liu
authors: Na
authors: N
authors: Li
authors: Yunyun
authors: Y
authors: Yuan
authors: Huili
authors: H
authors: Lu
authors: Xiaoyan
authors: X
authors: Wu
authors: Caihong
authors: C
authors: Zhou
authors: Min
authors: M
authors: He
authors: Haoran
authors: H
authors: Su
authors: Meng
authors: M
authors: Zhang
authors: Jia
authors: J
authors: Wang
authors: Bao
authors: B
authors: Wang
authors: You
authors: Y
authors: Wang
authors: Dawei
authors: D
authors: Ma
authors: Yang
authors: Y
authors: Ye
authors: Hans-Christoph
authors: HC
authors: Weiss
authors: Ernst R F
authors: ER
authors: Gesing
authors: Jiayu
authors: J
authors: Liao
authors: Ming-Wei
authors: MW
authors: Wang
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D003503:Cyclobutanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017930:Genes, Reporter; D000067757:Glucagon-Like Peptide-1 Receptor; D057809:HEK293 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D015394:Molecular Structure; D055668:Photochemical Processes; D010795:Phthalic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D018027:Receptors, Glucagon / Q000819:agonists*; D020218:Response Elements; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C570911:1,3-bis(4-isobutyramidobenzamido)-2,4-bis(3-methoxy-4-(thiophene-2-carbonyloxy)phenyl)cyclobutane-1,3-dicarboxylic acid; D003503:Cyclobutanes; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D010795:Phthalic Acids; D018027:Receptors, Glucagon