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.
