Chemical Properties
White Solid
Usage
A sodium-glucose transporter 2 inhibitor.
Usage
therapeutic for diabetes I or II, and hyperglycemia
Description
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.
Originator
Bristol-Myers Squibb (United States)
History
Dapagliflozin (brand name farxiga) was authorized for medical use in the European Union in November 2012. It was approved for medical use in the United States in January 2014.
In 2020, the US FDA expanded the indications for dapagliflozin to include treatment for adults with heart failure with reduced ejection fraction to reduce the risk of cardiovascular death and hospitalization for heart failure.
In April 2021, the FDA expanded the indications for dapagliflozin to include reducing the risk of kidney function decline, kidney failure, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease who are at risk of disease progression.
In February 2023, the EU authorized dapagliflozin for extended use to cover heart failure patients across the full spectrum of left ventricular ejection fraction (LVEF), including those with mildly reduced and preserved ejection fraction.
Uses
A sodium-glucose transporter 2 inhibitor.
Uses
therapeutic for diabetes I or II, and hyperglycemia
Definition
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.
Clinical Use
Selective and reversible inhibitor of sodium-glucose
co-transporter 2:
Treatment of type 2 diabetes
in vitro
ec50 values of 1.1 nm for hsglt2 and 1.4 μm for hsglt1 determined for dapagliflozin corresponded to 1200-fold selectivity for sglt2 as compared with phlorizin’s 10-fold selectivity. dapagliflozin inhibitory potencies against rat sglt (rsglt)2 and hsglt2 were comparable, but the selectivity of dapagliflozin for rsglt2 versus rsglt1 decreased to 200-fold [1].
in vivo
in vivo, dapagliflozin acutely induced renal glucose excretion in diabetic and normal rats, improved glucose tolerance in normal rats, as well as reduced hyperglycemia in zucker diabetic fatty rats after single oral doses ranging between 0.1 and 1.0 mg/kg [2].
Metabolism
Dapagliflozin is extensively metabolised, primarily
to dapagliflozin 3-O-glucuronide, which is an
inactive metabolite. The formation of dapagliflozin
3-O-glucuronide is mediated by UGT1A9, an enzyme
present in the liver and kidney, and CYP-mediated
metabolism was a minor clearance pathway in humans.
About 75% of the dose is excreted in the urine and 21%
in the faeces.
References
[1] meng w, ellsworth ba, nirschl aa, mccann pj, patel m, girotra rn, wu g, sher pm, morrison ep, biller sa, zahler r, deshpande pp, pullockaran a, hagan dl, morgan n, taylor jr, obermeier mt, humphreys wg, khanna a, discenza l, robertson jg, wang a, han s, wetterau jr, janovitz eb, flint op, whaley jm, washburn wn. discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (sglt2) inhibitor for the treatment of type 2 diabetes. j med chem. 2008 mar 13;51(5):1145-9.
[2] han s, hagan dl, taylor jr, xin l, meng w, biller sa, wetterau jr, washburn wn, whaley jm. dapagliflozin, a selective sglt2 inhibitor, improves glucose homeostasis in normal and diabetic rats. diabetes. 2008 jun;57(6):1723-9.
[3] bailey cj, iqbal n, t'joen c, list jf. dapagliflozin monotherapy in drug-na?ve patients with diabetes: a randomized-controlled trial of low-dose range. diabetes obes metab. 2012 oct;14(10):951-9.
