Abstract:
:A series of novel C-aryl glucosides with substituents at the 3'-position or cyclization at 3', 4'-positions of the distal aryl ring were designed and synthesized, which might decrease the oxidative metabolism of dapagliflozin. Preliminary evaluation for hypoglycemic effect and the risk of hypoglycemia were carried out both in normal and in streptozotocin-induced diabetic mice. Among the synthesized compounds, compound 19a exerted potency-similarity with dapagliflozin and triggered the hypoglycemic effect in a dose-dependent manner. Besides, compound 19a, even at the high dose of 10 mg/kg, revealed a low risk of hypoglycemia. In further studies, 19a exhibited sustained antihyperglycemic effect without particular side-effects in 30-day chronic diabetic mice studies. Moreover, histological changes in the pancreas of diabetic mice indicated 19a might protect pancreatic β-cell from apoptosis by reducing the damage of glucotoxicity. All of these results demonstrated that compound 19a, with excellent in vivo pharmacological activity and safety profile, was considered to be a promising drug candidate for the treatment of diabetes mellitus.
journal_name
Chem Biol Drug Desjournal_title
Chemical biology & drug designauthors
Li Z,Wang X,Xu X,Qiu Q,Jiao L,Huang W,Qian Hdoi
10.1111/cbdd.12547subject
Has Abstractpub_date
2015-10-01 00:00:00pages
764-75issue
4eissn
1747-0277issn
1747-0285journal_volume
86pub_type
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