Discovery and biological evaluation of novel G protein‐coupled receptor 119 agonists for type 2 diabetes. Issue 4 (10th February 2019)

• Record Type: Journal Article
• Authors: Zhou, Ying; Wang, Youzhi; Zhang, Leilei; Tang, Chunlei; Feng, Bainian
• Is Part Of: Archiv der Pharmazie. Volume 352:Issue 4(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-02-10
• Subjects: agonistic activity -- biological evaluation -- GPR119 -- synthesis -- type 2 diabetes; Pharmaceutical chemistry -- Periodicals; Pharmacology -- Periodicals; 615.19
• DOI: 10.1002/ardp.201800267
• Languages: English
• ISSNs: 0365-6233

Abstract

Abstract: G protein‐coupled receptor 119 (GPR119) is a member of the GPCR family promising to be the target for type 2 diabetes mellitus (T2DM) treatment. In this work, 30 novel compounds were designed, synthesized, and evaluated by in vitro cAMP activation assay, where compoundsII–14 andII–18 showed the best potency with EC50 values of 69 and 99 nM, respectively. In the oral glucose tolerance test, compoundII–18 showed even more efficacious activity in lowering blood excursions than MBX‐2982 at a fixed dose of 30 mg/kg. Here, we report that compoundII–18 with its excellent agonistic activity and its orally effective activity in decreasing blood glucose deviations may serve as a potent GPR119 agonist for the treatment of T2DM. Abstract : A series of novel orally bioavailable small‐molecule GPR119 agonists with improved potency and moderate physiochemical characteristics were designed, synthesized, and biologically evaluated. Among them, the most promising compoundII‐18 showed an EC50 value of 69 nM in in vitro cAMP assays and effectively lowered blood glucose excursions assessed by oral glucose tolerance test of normal mice.