Dapagliflozin

Bezeichnung:Dapagliflozin

CAS-Nr461432-26-8

Englisch Name:Dapagliflozin

CBNumberCB91011730

SummenformelC21H25ClO6

Molgewicht408.88

MOL-Datei461432-26-8.mol

Dapagliflozin physikalisch-chemischer Eigenschaften

Schmelzpunkt	55-58°C
Siedepunkt	609.0±55.0 °C(Predicted)
Dichte	1.349
storage temp.	2-8°C
Löslichkeit	DMSO (Slightly), Methanol (Slightly)
pka	13.23±0.70(Predicted)
Aggregatzustand	Solid
Farbe	White to Pale Yellow
Stabilität	Hygroscopic

Gefahreninformationscode (GHS)

Dapagliflozin Chemische Eigenschaften,Einsatz,Produktion Methoden

Beschreibung
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.
Beschreibung
Inhibiting renal glucose reabsorbtion through the sodium-glucose cotransporter (SGLT) offers an insulin-independent alternative to controlling blood glucose concentrations in patients with type 2 diabetes. While the majority of glucose is reabsorbed from glomerular filtrate by SGLT2, which is predominantly expressed in the kidney S1 segment of the proximal tubule, SGLT1 reabsorbs glucose in the distal S3 segment of the renal proximal tubule as well as from the small intestine. Dapagliflozin is a first generation, selective SGLT inhibitor that blocks glucose transport with about 100-fold selectivity for SGLT2 (K_i = 6 nM; EC₅₀ = 1.1 nM) over SGLT1 (K_i = 390 nM). After single oral doses ranging from 0.1 to 1.0 mg/kg, dapagliflozin increases urinary glucose excretion in both normal and diabetic rats, improves glucose tolerance in normal rats, and reduces hyperglycemia in Zucker diabetic fatty rats. Within two weeks of treating diabetic rats with 0.1 to 1.0 mg/kg dapagliflozin, fasting and fed glucose levels have been shown to be significantly lowered as a result of increased glucose utilization accompanied by reduced glucose production.
Chemische Eigenschaften
White Solid
Originator
Bristol-Myers Squibb (United States)
Verwenden
therapeutic for diabetes I or II, and hyperglycemia
Verwenden
A sodium-glucose transporter 2 inhibitor.
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.
Trademarks
Forxiga
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].
target
hSGLT2
Stoffwechsel
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.
Einzelnachweise
[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-naïve patients with diabetes: a randomized-controlled trial of low-dose range. diabetes obes metab. 2012 oct;14(10):951-9.

Dapagliflozin Upstream-Materialien And Downstream Produkte

Dapagliflozin Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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