Corresponding author: Stefan Balkanski ( st.balkanski@gmail.com ) Academic editor: Plamen Peikov
© 2021 Stefan Balkanski.
This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Citation:
Balkanski S (2021) Dapagliflozin – structure, synthesis, and new indications. Pharmacia 68(3): 591-596. https://doi.org/10.3897/pharmacia.68.e70626
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Dapagliflozin is a sodium-glucose co-transporter-2 (SGLT2) inhibitors used in the treatment of patients with type 2 diabetes. An aryl glycoside with significant effect as glucose-lowering agents, Dapagliflozin also has indication for patients with Heart Failure and Chronic Kidney Disease. This review examines the structure, synthesis, analysis, structure activity relationship and uses of the product. The studies behind this drug have opened the doors for the new line of treatment – a drug that reduces blood glucoses, decreases the rate of heart failures, and has a positive effect on patients with chronic kidney disease.
Dapagliflozin, SGLT2-inhibitor, diabetes, heart failure
C-glycosides have a remarkable rank in medicinal chemistry as they are considered as universal natural products (Qinpei and Simon 2004). Selective sodium-dependent glucose cotransporter 2 (SGLT-2) inhibitors are potent medicinal candidates of aryl glycosides that are functional against diabetes (
IUPAC name (2S,3R,4R,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol;(2S)-propane-1,2-diol;hydrate.
Dapagliflozin is an approved drug by U.S. Food and Drug Administration (FDA). Dapagliflozin is a representative of SGLT-2 inhibitors, actively considered to cure diabetes type 2. Thus, methodology of dapagliflozin synthesis has rarely published (
Jun et al. has reported a few improvements to the scheme 1. In the improved methodology scheme 2, trimethylsilyl chloride was added to gluconolactone 7 in the presence of N-methylmorpholine and tetrahydrofuran THF (
Zheng et al. designed the production methodology of dapagliflozin by introducing NO donor group at the last steps of general route of dapagliflozin synthesis (scheme 1). Novel hybrids achieved by the combination of dapagliflozin and NO donor, having excellent dual characteristics of anti-hyperglycemic and anti-thrombosis. The figure 2 represent the modifiable site (4-position) of dapagliflozin.
Scheme 3 has shown the formation strategy of new hybrids of nitric oxide with dapagliflozin. During the synthesis process, the compound 6 was treated with BBr3 that result in the formation of phenol 10, which was further subjected to condensation with bromoalkane and then undergo hydrolysis and produce 11 intermediates. Target compound was obtained by the reacting 11 with silver nitrate in acetonitrile (
Lin et al. fabricated green route (scheme 4) for the production of dapagliflozin. 5-bromo-2-chlorobenzoic acid 12 and gluconolactone were utilized to initiate the synthesis. By taking BF3.Et2O in catalytic amount to produce 13, overall yield of 76% was obtained in one-pot way via considering the Friedel-Craft acylation and ketallization. There was no need to do work-up operations to separate the diaryl ketal 13 as it was easily crystallized from the mixture. Compound 14 was produce as a result of condensation between 13 and 3. Overall yield of 68% of compound 15 was produced by the deprotection of silyl group in ethyl alcohol media. In THF presence, single crystals of 15 was achieved and characterized by XRD-analysis. High yield of dapagliflozin was obtained after the reduction of 15 that was carried out by triethylsilane in the presence of boron trifluoride diethyl etherate in dichloromethane. Upon crystallization from the mixture having heptane and ethyl acetate, greater than 98% pure dapagliflozin was produced by green synthetic pathway (
Manasa et al. has reported the reverse phase HPLC protocol to analyze the dapagliflozin in active pharmaceutical ingredients. To conduct this analysis, a BDS column was maintained at ambient temperature, mobile phase was prepared by utilizing the mixture of acetonitrile and phosphoric acid, PDA detectors were used, and detection noted at 245 nm. Manasa et al. estimate the stability of dapagliflozin by considering degradation in the presence of heat, UV, acidic, alkaline, and neutral conditions. For degradation studies, he treated dapagliflozin with acidic solution, alkali, heat, water and UV rays. Table
The structure-activity relationship in the structure shown in (figure 2) can be assessed by considering the linkage at 4-position in dapagliflozin, the linking of NO donor (
Xuekun et al. reported that coupling of various substituents at the distal aryl ring of dapagliflozin has paved a synthethic path towards a series of novel hybrids of C-aryl glycosides and their estimation against hypoglycemic and type 2 diabeteic rats has confirmed their anit-diabetic and anti-hyperglycemic activity. Introduction of electon donating and electron withdrawing groups impart special charactristic to dapagliflozin. Experimental results demonstrated that when the distal aryl ring is occupied by electron donating group, normal mice has reported imrpoved tolerance againt glucose, whereas this tolerance destroyed in the presence of electron withdring group (Figure
Gerg et al. stated that oral medication of dapagliflozin is given to patients having diabetes, which is inhibitor of sodium-glucose cotransporter 2. Increase in glucose rich urinary excretion and reduction of glucose level in blood has been caused by dapagliflozin as it suppresses the SGLT-2 transporter proteins and reduce the reabsorption of glucose in renal proximal tubules of nephron. The mode of action of dapagliflozin do not depend on the secretion of insulin or its action. When dapagliflozin used in combination with anti-hyperglycemic drugs, it gives complementary treatment. Findings collected from many clinical trials with dapagliflozin (mono or dual therapy) have clearly shown reduction in the body weight, glycosylated based hemoglobin and glucose concentration in fasting plasma. A very less chances of hypoglycemia has been reported by the usage of dapagliflozin. The patients having moderate or severe renal dysfunction are not treated with dapagliflozin drug. Dapagliflozin is recommended as a safe drug to cure type 2 diabetes because of its ubiquitous mode of action, high efficacy and good tolerability profile. Although diabetic complications observed during medication of dapagliflozin are still be evaluated (
Heart failure stays the principal cause of death and morbidity in advanced nations with an estimated pervasiveness of around 1–2% and hitting >10% among patients that are more than 70 years old (
Large clinical preliminaries including patients with type 2 diabetes have shown that inhibitors of sodium–glucose cotransporter 2 (SGLT2) decrease the danger of hospitalization for cardiovascular breakdown (Sarafidis et al. 2015;
In May 2020, the U.S. Food and Drug Administration approves dapagliflozin oral tablets for adults with heart failure with reduced ejection fraction to reduce the risk of cardiovascular death and hospitalization for heart failure. (
The definition and classification of chronic kidney disease (CKD) have evolved over time, but current international guidelines define this condition as decreased kidney function shown by glomerular filtration rate (GFR) of less than 60 mL/min per 1·73 m2, or markers of kidney damage, or both, of at least 3 months duration, regardless of the underlying cause. Diabetes and hypertension are the main causes of CKD in all high-income and middle-income countries, and also in many low-income countries. Incidence, prevalence, and progression of CKD also vary within countries by ethnicity and social determinants of health, possibly through epigenetic influence. Many people are asymptomatic or have non-specific symptoms such as lethargy, itch, or loss of appetite. (
A study conducted with 4304 participants concludes that among patients with chronic kidney disease, regardless of the presence or absence of diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes was significantly lower with dapagliflozin than with placebo. (
In April 2021 the U.S. Food and Drug Administration approves dapagliflozin oral tablets to reduce 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. (
Genital contaminations are by a wide margin the commonest symptom of dapagliflozin. Genital effects include vulvovaginitis and balanitis. Pooled data collected after analyzing 12 studies shown that when study subject was treated dapagliflozin at a dose of 5mg, 10 mg and placebo, resulted in the infection rate of 5.7%, 4.8% and 0.9% respectively, shown in graph 1. The first six months have shown mild infections with less chances of reoccurrence with long term therapy. There was a higher risk of emergent infections with those having previous history. These diseases reacted to standard oral anti-infection treatment (
The usage of dapagliflozin has reported infections of urinary tract. Patients administered with dapagliflozin of 5mg, 10mg and placebo demonstrated percentage of infection of 5.7%, 4.3% and 3.7% respectively, graph 2. These infections were not acute and reported in response to anti-diabetic therapy followed by oral medication (
Monotherapy of dapagliflozin nor therapy in combination with metformin linked with hypoglycemia. When medication of dapagliflozin pursued along with hypoglycemic agents (insulin and SUs), it increases the risk factor for hypoglycemia. It is recommended that at the beginning of therapy, hypoglycemic risks can be minimized by reducing the dose of other agents during dapagliflozin medication (
Dapagliflozin-drug indicated for manifesting hyperglycaemia which is a sodium-glucose cotransporter 2 inhibitor. It helps to control glycaemic index by hindering glucose resorption in proximal tubule of the nephron, when integerated with dietary improvements and exercises. It has decreased the rate of hospitalization due to heart dysfunction in diabetic patients suffering from heart disorders. The studies have opened the doors for the new line of treatment, using this drug. The need of an hour is to search possibilities for the effective pharmaceutical that can address this dual epidemic, and specifically decreases the rate heart failures and positive effect on patients with chronic kidney disease.