INTRODUCTION
Diabetes mellitus is a state of chronic hyperglycemia secondary to multiple pathophysiological defects that include not only a dysfunction of the β-cells and α-cells resulting in impaired insulin and glucagon actions but also defective incretin axis, neurohormonal derangement in the brain as well as an increase in the glucose reabsorption in the kidneys. An understanding of these multiple etiological defects has stimulated researchers to search for novel agents targeting each of these mechanisms to optimize and individualize treatment of diabetes in current times. The latest agents to be added to our armamentarium are the sodium-glucose cotransporter-2 inhibitors (SGLT-2 inhibitors), commonly known as the gliflozins that primarily work by reducing the excessive renal glucose reabsorption that occurs in patients with diabetes. Following the discovery of phlorizin, the first natural SGLT-2 inhibitor, a number of synthetic glucoside analogs have been developed and are being used today while the search for newer agents is still ongoing. This chapter will introduce readers to the history and evolution of early-generation SGLT-2 inhibitors derived from natural plants leading to the development of the currently used prototypes of this class of agents and will give a glimpse into the recent advancement on the futuristic molecules in the pipeline.2
THE FIRST NATURAL SGLT-2 INHIBITOR—PHLORIZIN AND ITS GLUCOSIDE ANALOGS
The first recognized natural substance with SGLT-2 inhibitory action was phlorizin, a dihydrochalcone compound isolated from barks of apple trees way back in 1835. Initially regarded as a treatment option for fevers, malaria and infectious diseases owing to its similarity with cinchona and willow tree extracts, the evolution of phlorizin as an inhibitor of renal glucose reabsorption that caused increase in urinary glucose excretion was reported almost five decades later by Chasis et al. The relationship between the glucose transport system of the proximal tubular brush border epithelium and phlorizin came to be established in 1970s. Several in vivo studies on diabetic animal models showed reduced fasting and/or postprandial blood glucose levels and increased insulin sensitivity following phlorizin administration. Katsuno et al. reported inhibition of both human SGLT-1 and SGLT-2 with phlorizin, with the inhibitory constant (Ki) values of 151 nM and 18.6 nM, respectively. In spite of its sufficient SGLT inhibitory actions, certain critical drawbacks disqualified phlorizin from further use as an antihyperglycemic agent. Most prominent of these was the low therapeutic selectivity of phlorizin for both SGLT-1 and SGLT-2. By inhibiting SGLT-1 primarily localized in the small intestine, phlorizin was shown to cause several gastrointestinal side effects, such as diarrhea, dehydration and malabsorption. Also, its absorption from small intestine was quite poor owing to its low oral bioavailability. Besides, phloretin, α-glycosidase catalyzed hydrolytic metabolite of phlorizin, strongly inhibits the ubiquitous glucose transporter 1 (GLUT1), which then may obstruct glucose uptake in various tissues.
These drawbacks lead to a quest for developing novel analogs of phlorizin that would have better stability, bioavailability, and higher selectivity for SGLT-2 receptors. Researchers then focused on the O-glucoside analogs of phlorizin eventually developing T-1095, an oral selective inhibitor of SGLT-2 that undergoes extensive hepatic metabolism into its active metabolite T-1095A. This metabolite demonstrated dose-dependent reduction in urinary glucose reabsorption with consequent reduction in blood glucose, 3triggering development of numerous other similar O-glucoside derivatives such as sergliflozin, remogliflozin and AVE2268 over the next few years. Though these agents minimized glucosidase-mediated degradation and increased systemic exposure, they were pharmacokinetically unstable and had incomplete pharmacological selectivity for SGLT-2. This eventually led to phasing out of these agents and shifted research toward other derivatives of phlorizin.
The first C-glucoside analogs of phlorizin were developed in 2000 which further lead to development of the currently used molecules—the first one being dapagliflozin, developed in 2008 by Meng et al. with lipophilic ethoxy substituents at position 4 on the B-ring of phlorizin as shown here in Figure 1. Dapagliflozin showed a dose-dependent glucosuric response and significantly reduced fasting and postprandial blood glucose levels as well as hemoglobin A1c (HbA1c) with significant weight loss and a 1,200-fold higher selectivity for human SGLT-2 versus SGLT-1 (IC50: 1.12 nM vs. 1,391 nM). Dapagliflozin was introduced and became commercially available first in Europe in 2012 followed by the United States Food and Drug Administration (USFDA) approval in January 2014 paving its way for use in US and eventually globally thereafter.
Canagliflozin, a thiophene derivative of C-glucoside was approved by the USFDA in 2013 with similar antihyperglycemic properties and an over 400-fold difference in selectivity for SGLT-2 versus SGLT-1 (IC50: 2.2 nM vs. 910 nM).
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The third gliflozin to hit the global markets was empagliflozin characterized by the highest, i.e. 2,700-fold selectivity for SGLT-2 versus SGLT-1. Various other gliflozins such as ipragliflozin, tofogliflozin and luseogliflozin have since been developed, mainly by the Japanese, while others such as ertugliflozin and LX-4211 (sotagliflozin—a dual SGLT-2/SGLT-1 inhibitor) are also now the latest entrants into this arena.
SOPHORA FLAVESCENS (FABACEAE)
Sophora flavescens (S. flavescens) or the shrubby sophora is a popular Chinese shrub belonging to the pea family Fabacea. Its root, known as “Kushen”, being rich in alkaloids and flavonoids, has traditionally been used for treating numerous diseases including dysentery, fever, jaundice, leukorrhea, scabies, pyogenic skin infections, swelling and also pain. Studies have also proven additional anti-inflammatory, antitumor, antianaphylactic, antiasthmatic, antimicrobial and immunoregulatory as well as cardiovascular protective effects. Research has further demonstrated that the methanol extract of this plant has a potent SGLT inhibitory activity. Three of these extracts, namely—(1) maackiain; (2) variabilin; and (3) formononetin, with isoflavonoid-based structures having a hydroxyl functional group, demonstrated exclusive SGLT-2 inhibitory activity. Also, flavanone compounds, the most potent being kurarinone and sophoraflavanone G, demonstrated extensive inhibition of both SGLT-2 and SGLT-1, with increased selectivity for SGLT-2 attributable to the common lavandulyl functional group at the C-8 position. Currently, SGLT-2 inhibitory effects of all nine isolated compounds of isoflavanoid glycosides from roots of S. flavescens have been demonstrated.
CONCLUSION
The identification of renal glucose reabsorption as an important pathophysiological contributor to hyperglycemia paved the way for SGLT-2 inhibition as a promising therapeutic strategy for treatment of type 2 diabetes mellitus. The last few years have shown the introduction of various SGLT-2 inhibitors derived from the natural active compound phlorizin, approved for use in type 2 diabetes both as monotherapy and as combination therapy with other antidiabetic 5agents including insulin. A number of these agents are now available globally while newer ones are being constantly developed and studied.
SUGGESTED READING
- Abdul-Ghani MA, DeFronzo RA. Inhibition of renal glucose absorption: A novel strategy for achieving glucose control in type 2 diabetes mellitus. Endocr Pract. 2008;14(6):782–90.
- Baynes JW. Role of oxidative stress in development of complications in diabetes. Diabetes. 1991;40(4):405–12.
- Bays H. Sodium glucose co-transporter type 2 (SGLT2) inhibitors: Targeting the kidney to improve glycemic control in diabetes mellitus. Diabetes Ther. 2013;4(2):195–220.
- Bickel M, Brummerhop H, Frick W, et al. Effects of AVE2268, a substituted glycopyranoside, on urinary glucose excretion and blood glucose in mice and rats. Arzneimittelforschung. 2008;58(11):574–80.
- Chasis H, Jolliffe N, Smith HW. The action of phlorizin on the excretion of glucose, xylose, sucrose, creatinine and urea by man. J Clin Invest. 1933;12(6):1083–90.
- Derdau V, Fey T, Atzrodt J. Synthesis of isotopically labelled SGLT inhibitors and their metabolites. Tetrahedron. 2010;66(7):1472–82.
- Ehrenkranz JR, Lewis NG, Kahn CR, et al. Phlorizin: A review. Diabetes Metab Res Rev. 2005;21(1):31–8.
- Gorboulev V, Schürmann A, Vallon V, et al. Na+-D-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion. Diabetes. 2012;61(1):187–96.
- Grempler R, Thomas L, Eckhardt M, et al. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: Characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes Metab. 2012;14(1):83–90.
- Han S, Hagan DL, Taylor JR, et al. Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes. 2008;57(6):1723–9.
- Hung HY, Qian K, Morris-Natschke SL, et al. Recent discovery of plant-derived anti-diabetic natural products. Nat Prod Rep. 2012;29(5):580–606.
- Meng W, Ellsworth BA, Nirschl AA, et al. 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;51(5):1145–9.
- Mudaliar S, Polidori D, Zambrowicz B, et al. Sodium-glucose cotransporter inhibitors: Effects on renal and intestinal glucose transport: From bench to bedside. Diabetes Care. 2015;38(12):2344–53.
- Nomura S, Sakamaki S, Hongu M, et al. Discovery of canagliflozin, a novel C-glucoside with thiophene ring, as sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus. J Med Chem. 2010;53(17): 6355–60.
- Rahmoune H, Thompson PW, Ward JM, et al. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes. 2005;54(12):3427–34.
- Rieg T, Masuda T, Gerasimova M, et al. Increase in SGLT1-mediated transport explains renal glucose reabsorption during genetic and pharmacological SGLT2 inhibition in euglycemia. Am J Physiol Renal Physiol. 2014;306(2):F188–93.
- Rosenstock J, Aggarwal N, Polidori D, et al. Dose-ranging effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes. Diabetes Care. 2012;35(6):1232–8.
- Rossetti L, Lauglin MR. Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J Clin Invest. 1989;84(3):892–9.
- Sato S1, Takeo J, Aoyama C, et al. Na+-glucose cotransporter (SGLT) inhibitory flavonoids from the roots of Sophoraflavescens. Bioorg Med Chem. 2007;15(10):3445–9.
- Vallon V, Platt KA, Cunard R. SGLT2 mediates glucose reabsorption in the early proximal tubule. J Am Soc Nephrol. 2011;22(1):104–12.
- Vallon V. The mechanisms and therapeutic potential of SGLT2 inhibitors in diabetes mellitus. Annu Rev Med. 2015;66:255–70.
- Vestri S, Okamoto MM, de Freitas HS, et al. Changes in sodium or glucose filtration rate modulate expression of glucose transporters in renal proximal tubular cells of rat. J Membr Biol. 2001;182(2):105–12.
- Vick H, Diedrich DF, Baumann K. Reevaluation of renal tubular glucose transport inhibition by phlorizinanalogs. Am J Physiol. 1973;224(3):552–7.
- White JR. Apple trees to sodium glucose co-transporter inhibitors: a review of SGLT2 inhibition. Clin Diabetes. 2010;28(1):5–10.
- Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev. 2011;91(2):733–94.