Dapagliflozin

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Dapagliflozin
Dapagliflozin structure.svg
Systematic (IUPAC) name
(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol
Clinical data
Trade names Forxiga, Farxiga
AHFS/Drugs.com UK Drug Information
Licence data EMA:Link, US FDA:link
Pregnancy
category
  • US: C (Risk not ruled out)
Legal status
Routes of
administration
Oral
Identifiers
CAS Number 461432-26-8 N
ATC code A10BX09 (WHO)
PubChem CID: 9887712
IUPHAR/BPS 4594
DrugBank DB06292 N
ChemSpider 8063384 YesY
UNII 1ULL0QJ8UC YesY
ChEBI CHEBI:85078 YesY
ChEMBL CHEMBL429910 YesY
Synonyms BMS-512148
Chemical data
Formula C21H25ClO6
Molecular mass 408.873 g/mol
  • Clc1ccc(cc1Cc2ccc(OCC)cc2)[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O
  • InChI=1S/C21H25ClO6/c1-2-27-15-6-3-12(4-7-15)9-14-10-13(5-8-16(14)22)21-20(26)19(25)18(24)17(11-23)28-21/h3-8,10,17-21,23-26H,2,9,11H2,1H3/t17-,18-,19+,20-,21+/m1/s1 YesY
  • Key:JVHXJTBJCFBINQ-ADAARDCZSA-N YesY
 NYesY (what is this?)  (verify)

Dapagliflozin (INN/USAN,[1] trade name Farxiga in the US and Forxiga in the EU) is a drug of the gliflozin class, used to treat type 2 diabetes. It was developed by Bristol-Myers Squibb in partnership with AstraZeneca.

Medical uses

In July 2011 a US Food and Drug Administration (FDA) committee recommended against approval until more data were available.[2]

The FDA approved dapagliflozin on January 8, 2014 for glycemic control, along with diet and exercise, in adults with type 2 diabetes.[3] The FDA approved the combination product dapagliflozin and metformin hydrochloride extended-release, called Xigduo XR, in October 2014.[4]

In April 2012, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency issued a positive opinion on the drug. It is now marketed in a number of European countries.

Side effects

Since dapagliflozin leads to heavy glycosuria (sometimes up to about 70 grams per day) it can lead to rapid weight loss and tiredness. The glucose acts as an osmotic diuretic (this effect is the cause of polyuria in diabetes) which can lead to dehydration. The increased amount of glucose in the urine can also worsen the infections already associated with diabetes, particularly urinary tract infections and thrush (candidiasis). Dapagliflozin is also associated with hypotensive reactions. There are concerns it may increase the risk of diabetic ketoacidosis.[5]

Mechanism of action

Dapagliflozin inhibits subtype 2 of the sodium-glucose transport proteins (SGLT2) which are responsible for at least 90% of the glucose reabsorption in the kidney. Blocking this transporter mechanism causes blood glucose to be eliminated through the urine.[6] In clinical trials, dapagliflozin lowered HbA1c by 0.6 versus placebo percentage points when added to metformin.[7]

Selectivity

The IC50 for SGLT2 is less than one thousandth of the IC50 for SGLT1 (1.1 versus 1390 nmol/l), so that the drug does not interfere with intestinal glucose absorption.[8]

Research

Clinical trials to assess effectiveness for patients with type 1 diabetes are underway.[9][10]

References

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External links

  1. Statement on a nonproprietory name adopted by the USAN council
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  6. Prous Science: Molecule of the Month November 2007
  7. UEndocrine: Internet Endocrinology Community
  8. Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel 2008/2009
  9. Efficacy and Safety of Dapagliflozin, Added to Therapy of Patients With Type 2 Diabetes With Inadequate Glycemic Control on Insulin, ClinicalTrials.gov, April 2009
  10. Trial Details for Trial MB102-020, Bristol-Myers Squibb, May 2009