title: Synthesis and biological evaluation of glucagon-like peptide-1 receptor agonists.
abstract: In this study, a series of fused-heterocyclic derivatives were systematically designed and synthesized using an efficient route, and evaluated in terms of GLP-1R agonist activity. We employed short synthetic steps and reactions that are tolerant of the presence of various functional groups and suitable for parallel operations to enable the rapid generation of libraries of diverse and structurally complex small molecules. Of the compounds synthesized, 3-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a] pyridin-2-yl)phenyl methanesulfonate (8e) was the most potent agonist with an EC50 of 7.89 μM, and thus is the compound with the greatest potential for application. These findings represent a valuable starting point for the design and discovery of small-molecule GLP-1R agonists that can be administered orally.
authors.affiliation: School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, China.
authors.forename: Yu-Juan
authors.initials: YJ
authors.lastname: Zhang
authors.forename: Liu-Lan
authors.initials: LL
authors.lastname: Shen
authors.forename: Hyae-Gyeong
authors.initials: HG
authors.lastname: Cheon
authors.forename: Yong-Nan
authors.initials: YN
authors.lastname: Xu
authors.forename: Jin-Hyun
authors.initials: JH
authors.lastname: Jeong
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D015394:Molecular Structure; D011726:Pyridinium Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D018027:Receptors, Glucagon / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D011726:Pyridinium Compounds; D018027:Receptors, Glucagon; D054852:Small Molecule Libraries