C-芳基葡糖苷SGLT2抑制剂的最新进展

Title:Recent Developments of C-Aryl Glucoside SGLT2 Inhibitors

Volume: 23 Issue: 8

Author(s): Yang Zhang and Zhao-Peng Liu

Affiliation:

关键词: 抗糖尿病剂，C-芳基葡萄糖苷，糖尿病，葡萄糖，抑制剂，SGLT2，SGLT1，钠 - 葡萄糖协同转运蛋白2，2型糖尿病，2型糖尿病。

摘要: Sodium-glucose cotransporter 2 (SGLT2) is almost exclusively expressed in the proximal renal tubules. It is responsible for about 90% of the glucose reabsorption from tubular fluid. Selective inhibition of SGLT2 is expected to favor in the normalization of plasma glucose levels in T2DM patients through the prevention of renal glucose reabsorption and the promotion of glucose excretion from urine. Selective SGLT2 inhibitors have the merits to minimize the gastrointestinal side effects associated with SGLT1 inhibition, and selective SGLT2 inhibition may have a low risk of hypoglycemia. Since the C-aryl glucosides are metabolically more stable than the O-glucosides, numerous efforts have been made in the development of potent and selective C-aryl glucoside SGLT2 inhibitors, and a number of them are now used as anti-diabetes drugs in clinic or at various stages of clinical developments. Based on their structural features, in this review, these SGLT2 inhibitors are classified as three types: the phenyl/arylmethylphenyl C-glucosides, with an emphasis on the modifications on the proximal and/or the distal phenyl ring, and the spacer; the heteroarylmethylphenyl Cglucosides, with a replacement of the distal phenyl ring by a heterocycle like pyridazine, pyrimidine, thiophene and benzothiophene, thiazole, 1,3,4-thiadiazole, and triazolopyridinone; and the glucose-modified Caryl glucosides, including the glucose C-1 derived O-spiroketals, C-4 gem-difluoro analogues, C-5 and C-6 modified derivatives, dioxa-bicyclo[3.2.1]octane bridged ketals, the thioglucosides, and carbasugars. The structure-activity relationships (SARs) of each type along with their inhibitory potency against human SGLT2 and selectivity over human SGLT1 are discussed.

Cite this article as:

Yang Zhang and Zhao-Peng Liu , Recent Developments of C-Aryl Glucoside SGLT2 Inhibitors, Current Medicinal Chemistry 2016; 23 (8) . https://dx.doi.org/10.2174/0929867323666160210125747