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 (Lee et al. 2005; Lemaire 2012; Mironova et al. 2017). Embodiments of (SGLT-2) inhibitors include dapagliflozin, canagliflozin, empagliflozin and ipragliflozin, shown in Figure 1. It has molecular formula of C₂₄H₃₅ClO₉.

Figure 1. 

Manifestation and chemical structure of inhibitors of (SGLT-2).

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 (Ellsworth et al. 2002; Meng 2008). Scheme 1 have shown the general synthetic route for the synthesis of dapagliflozin. Gluconolactone 3 which was protected by trimethylsilyl TMS was treated with aryl lithium. Aryl lithium was obtained by reacting aryl bromide 2 (exchange of Li/Br) with n-BuLi. Methyl C-aryl glucoside 4 was produced by treatment of resulting mixture with methane sulfonic acid in the presence of methanol. Compound 4 was subjected to acetylation in the presence of Ac₂O, resulted in the formation of 5 followed by reduction of 5 to 6 with the help of Et₃SiH and BF₃.OEt₂. Finally, dapagliflozin 1 was produced via hydrolysis of 6 by LiOH (Deshpande et al. 2008; Meng 2008).

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 (Horton et al. 1981), followed by the formation of persilyated lactone 3. After completing the reaction of aryl bromide 2 with n-BuLi, added to persilyated lactone 3. Intermediate lactol 8 was produced by treating resulting reaction mixture with trifluoroacetic acid in aqueous form. Then ethyl C-aryl glycoside 9 yielded when subsequently compound 8 was subjected to methane-sulfonic acid in ethyl alcohol. Crude product 9 in the form of oil was secured after the screening of solvents. Jun et al. proposed that more than 98% pure 9 was collected as crystalline solvate after the crystallization of crude oil from n-propanol and n-heptane mixture (Yu et al. 2019). Moreover, Wang et al. proposed that a high extent of diastereoselectivity obtained after the reduction of tetra-O-unprotected methyl C-aryl glucoside by utilizing Et₃SiH and BF₃.Et₂O (Wang et al. 2014). The nature of active pharmaceutical ingredient is amorphous foam which is isolated after the reduction of 9. Production of cocrystalline complex facilitate the isolation and purification of API (Deng et al. 2017). It is concluded that more than 99.7% pure dapagliflozin produced in overall 79% yield, after the crystallization of a mixture consists of n-heptane and ethyl acetate (Yu et al. 2019).

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 (Li et al. 2018).

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 (Hu et al. 2019).

Scheme 2. 

Improved methodology proposed by Jun et al.

Scheme 1. 

Synthetic route for dapagliflozin synthesis reported from literature.

Scheme 3. 

Synthesis of hybrids of NO donor.

Scheme 4. 

Green route for the synthesis of dapagliflozin by Lin et al.

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 1 shows the percentage of degradation with all the mentioned medium (Sanagapati et al. 2014).

Figure 2. 

Conjugation of dapagliflozin an NO donor.

Figure 3. 

Introduction of substituents at distal aryl ring.

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 (Xu et al. 2011). One of the signaling molecules, nitric oxide is a notable molecule which has excellent signaling profile. The assortment of physiological cycles in cardiovascular system, including the restraint of platelet accumulation, unwinding of vascular smooth muscles, diminishing adherence and actuation of neutrophil is substantially accomplished by the action of NO (Guzik et al. 2003). SGLT-2 inhibitor coupling with donor of NO give rise to exotic hybrids, having dual pharmacological potential such as anti-hyperglycemic and anti-thrombosis and consequently mitigate the prevalence of cardiovascular issues (Palmer et al. 1989).

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 3). Upon administration of glusoce at a dose of 3 g.kg^-1 along with compound 13c in normal mice, increase in urniary glucose excretion has observed. This compound has shown excellent anti-huperglycemic activity by reducing fed blood glucose leveles in diabetic rats (Wang et al. 2015).

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.