Uses
Empagliflozin(864070-44-0) is a novel, potent and selective SGLT-2 inhibitor, improves glycaemic control and features of metabolic syndrome in diabetic rats.
Definition
ChEBI: A C-glycosyl compound consisting of a beta-glucosyl residue having a (4-chloro-3-{4-[(3S)-tetrahydrofuran-3-yloxy]benzyl}phenyl group at the anomeric centre. A sodium-glucose co-transporter 2 inhibitor u
ed as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Clinical Use
Selective and reversible inhibitor of sodium-glucose
co-transporter 2:Treatment of type 2 diabetes
Side effects
Empagliflozin(864070-44-0) had a low incidence of adverse reactions. Compared with the placebo group, the incidence of common adverse reactions was 2%, including urinary tract infection, female reproductive system fungal infection, upper respiratory tract infection, polyuria, dyslipidemia (dose-related low-density lipoprotein increased), arthralgia, fungal infection of male reproductive system, hypoglycemia (the incidence of hypoglycemia increased when empagliflozin was combined with insulin or sulfonylurea hypoglycemic drugs), nausea. Other adverse reactions less than 2% were common in thirst (polydipsia, polydipsia), hypovolemia, and renal dysfunction.
Synthesis
Commercial
5-iodo-2-chlorobenzoic acid (97) was first converted to
the corresponding acid chloride, prior to subjection to commercially
available fluorobenzene (98) under Friedel¨CCrafts conditions
to generate the desired fluorobenzophenone 99 in 94% yield after
isolation by recrystallization from aqueous isopropanol. The fluorobenzophenone
(99) was then reacted with commercially available
(S)-3-hydroxytetrahydrofuran (100) and potassium tertbutoxide
in THF to afford ethereal benzophenone 101. Next,
removal of the ketone functionality within 101 was achieved
through the use of 1,1,3,3-tetramethyldisiloxane (TMDS) in the
presence of aluminum chloride in toluene to deliver diaryl iodide
102. This iodide was subsequently converted to the corresponding
Grignard reagent and subjected to gluconolactone 103, giving rise
to an intermediate lactol which was then sequentially treated with
aqueous citric acid, methanolic HCl, and triethylsilyl hydride and
aluminum trichloride to ultimately furnish empagliflozin (XIII) in
73% yield across the four-step protocol.
Drug interactions
Potentially hazardous interactions with other drugs
None known
Metabolism
In vitro studies suggested that the main route
of metabolism is glucuronidation by the uridine
5'-diphospho-glucuronosyltransferases UGT2B7,
UGT1A3, UGT1A8, and UGT1A9Following administration of oral [14C]-empagliflozin
solution to healthy volunteers, approximately 96% of the
drug-related radioactivity was eliminated in faeces (41%)
or urine (54%). The majority of drug-related radioactivity
recovered in faeces was unchanged parent drug and
approximately half of drug-related radioactivity excreted
in urine was unchanged parent drug
Mode of action
Empagliflozin(864070-44-0) is an orally available competitive inhibitor of sodium-glucose co-transporter 2 (SGLT2; SLC5A2) with antihyperglycemic activity. Upon oral administration, empagliflozin selectively and potently inhibits SGLT2 in the kidneys, thereby suppressing the reabsorption of glucose in the proximal tubule. Inhibition of SGLT2 increases urinary glucose excretion by the kidneys, resulting in a reduction of plasma glucose levels in an insulin-independent manner. Inhibition of SGLT2 in the kidneys also suppresses the renal reabsorption of 1,5-anhydroglucitol (1,5AG). This lowers serum 1,5AG and neutrophil 1,5-anhydroglucitol-6-phosphate (1,5AG6P) levels, which may improve neutropenia and neutrophil dysfunction in patients with glycogen storage disease type Ib (GSD Ib). SGLT2, a transport protein exclusively expressed in the proximal renal tubules, mediates approximately 90% of renal glucose reabsorption from tubular fluid.
pubchem.ncbi.nlm.nih.gov/compound/Empagliflozin
