Дапаглифлозин

The Australian Therapeutic Goods Administration (TGA) and the European Commission approved dapagliflozin in October and November 2012, respectively, as an adjunct to diet and exercise for the treatment of type 2 diabetes. Dapagliflozin is a potentially attractive therapy due to its glucosesensitive and insulin-independent mechanism of action. It is a first-in-class selective SGLT2 inhibitor (IC₅₀=1.1 nM; selectivity vs. SGLT1 >1000) that lowers the renal threshold for reabsorption of glucose, allowing excess glucose to be eliminated via the kidneys. In normal rats, administration of dapagliflozin promotes dose-dependent excretion of up to 1900 mg of glucose over a 24 h period, with amaximal effect at 3 mg/kg. In a ratmodel of diabetes, pretreatment with the pancreatic toxin streptozotocin results in hyperglycemia that is reduced 55% by administration of a single 0.1 mg/kg dose of dapagliflozin compared with vehicle. Aryl O-glucoside SGLT2 inhibitors were early entrants into the clinic, but the aryl C-glucoside linkage found in dapagliflozin confers resistance to glucosidase-mediated metabolism leading to improved clinical utility relative to aryl O-glucosides. The modified carbohydrate–aglycone linkage required concomitant adjustment from an ortho- to a meta-substituted arylglucoside to achieve potent SGLT2 inhibition. Dapagliflozin was synthesized in several steps via reaction of an aryllithium with per-silylated gluconolactone to form the key C-glucoside linkage. An alpha-selective reduction of the resultant anomeric glycoside gave the desired beta-Carylglucoside. The main circulating (inactive) metabolite is the result of 3-O-glucuronidation of the glucosylmoiety. Of the minority metabolites, the main oxidative species result from O-dealkylation of the ethoxy-group and hydroxylation of the biarylmethane moiety.

White Solid

A sodium-glucose transporter 2 inhibitor.

ChEBI: A C-glycosyl comprising beta-D-glucose in which the anomeric hydroxy group is replaced by a 4-chloro-3-(4-ethoxybenzyl)phenyl group. Used (in the formo f its propanediol monohydrate) to improve glycemic ontrol, along with diet and exercise, in adults with type 2 diabetes.