Design, synthesis, and biological evaluation of 2‐(4‐(methylsulfonyl)phenyl)pyridine derivatives as GPR119 agonists. (12th September 2018)

• Record Type: Journal Article
• Authors: Zhou, Ying; Zhu, Xiaoyun; Zhang, Leilei; Tang, Chunlei; Feng, Bainian
• Is Part Of: Chemical biology & drug design. Volume 93:Number 1(2019)
• Page Start: 67
• Page End: 74
• Publication Date: 2018-09-12
• Subjects: 2‐(4‐(methylsulfonyl)phenyl)pyridine -- agonistic activity -- GPR119 -- synthesis -- type 2 diabetes; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.13380
• Languages: English
• ISSNs: 1747-0277

Abstract

Abstract: This study describes the design, synthesis, and biological evaluation of a series of novel small molecule GPR119 agonists with improved potency and moderate physiochemical characteristics. Among them, the most promising compounds19 and20 were obtained with EC50 values of 75 and 25 nM, respectively, in vitro cAMP assays and effectively decreased blood glucose excursion in oral glucose tolerance test (OGTT) of normal mice. Furthermore, in OGTT with type 2 diabetic mice induced by streptozotocin and high‐fat diet, compound19 also showed significant reduction in blood glucose level compared to vehicle control group, which demonstrated an attractive in vitro and in vivo profile for further development. Abstract : This study describes the design, synthesis, and biological evaluation of a series of novel orally bioavailable small molecule GPR119 agonists with improved potency and moderate physiochemical characteristics. Among them, the most promising compound 19 was obtained with EC50 values of 75 nM in in vitro cAMP assays and effectively lowered blood glucose excursion in oral glucose tolerance test (OGTT) of normal mice as well as type 2 diabetic mice induced by streptozotocin and high‐fat diet, and had high potency to be a new lead.