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Shakir 1 Canaglifiozin, a SGLT2 Inhibitor Reema Shakir Copyright 2013 Introduction: According to Centers of Disease Control (CDC), in the United States approximately 26 million people are affected by diabetes and approximately seven million of them are not aware. Also, approximately 79 million adults in the U.S. have prediabetes, in this condition glucose levels are higher than the normal but not high enough to be diabetes. In addition, CDC has predicted that by 2050, 1 in 3 people will have prediabetes. Usually a person is diagnosed 7 to 10 years after the onset of the disease and within this time deadly complication may have developed such as an increased risk for heart disease, blindness, kidney disease, strokes, amputations, and death. For these reasons, early diagnosis and effective treatment is vital for successful treatment. When food is eaten that contains carbohydrate, it is broken down in the stomach and digested into glucose, which is a type of sugar. Glucose is used by the cells to make Adenosine5’-triphosphate (ATP), which provided energy for the cells to carry out normal functions, through the process of glycolysis. Glucose transporter 2 (GLUT2), is located in pancreatic β-cell, has a high capacity for glucose but a low affinity and therefore it is able to detects the rise in the levels of glucose in the blood stream. The rise in blood glucose levels trigger the β-cells to release insulin, this hormone allows the cells such as, muscle and adipose, to uptake glucose from the blood stream (Nelson, 2008). If glucose is not metabolized by muscle and adipose cells, then glucose levels in the blood stream to keep rising, this constant rise can lead to diabetes.

Shakir 2 There are two main types of diabetes, diabetes mellitus type 1 (T1DM) and type 2 diabetes mellitus (T2DM). Type I diabetes results from an autoimmune damage of the β-cells in pancreas by the CD4+ T helper cells and CD8+ T cells (Cooke, 2008). Therefore glucose is not taken up by the cell this causes a rise of glucose in the blood stream, if not treated. Type 2 diabetes mellitus is more complex than T1DM, because in T2DM either the pancreatic β-cells are not producing enough insulin or the insulin receptors are less sensitive to the insulin, a condition called insulin resistance. In the early stages of T2DM, both blood glucose and insulin levels continue to rise but insulin is not able to cope with the gradual rise of glucose, therefore the β-cells in the pancreas produce less insulin. The body tries to get rid of glucose through the kidneys. Therefore people with diabetes have an increase in urine output (Hardman, 2011). In the kidneys, normally all the plasma glucose that enters the kidney is filtered into the nephrons through the glomeruli. Then all the plasma glucose is reabsorbed mainly by sodiumdependent glucose co-transporter 2 (SGLT2) from the tubular lumen and back into the blood. In a healthy person, the amount of glucose that passes through the proximal tubules is approximately 180g/day and most of this glucose is completely reabsorbed. But under hyperglycemic conditions, an increase in glucose concentration in the body increases the filtered glucose load. Glycosuria, the condition where glucose is present in the urine, occurs when the amount of glucose, which enters the kidneys, is above 260-350 mg/min (Hardman, 2011).Under hyperglycemic conditions the urinary glucose excretion (UGE) increases linearly, because the reabsorption process is saturated due to the large amount of glucose present. There are two types of Sodium-Dependent Glucose Co-transporters, SGLT1 and SGLT2, SGLT1 is mainly located in the trachea, heart, and intestine and SGLT 2 are only in the kidney, for this reason SGLT2 inhibitors are the best target for anti-diabetic agents (Nomura, 2010). The function of SGLT1 is

Shakir 3 to transport glucose found in tissues such as the small intestine to the blood stream and SGLT2 allows the reabsorption of renal glucose. It has been very difficult for doctors to treat patients with T2DM, mainly because many anti-diabetic drugs are not able to stop its progression. In most patients there is no known medication that is able to maintain the control of blood glucose for a long period of time. Therefore there is a demand for the development of new drugs with improved effectiveness and safety. A possible new treatment for T2DM is a SGLT2 inhibitor, which will decrease glucose reabsorption from the kidneys. For this reason SGLT2 inhibitors are the best target for antidiabetic agents. The characteristic of SGLT2 inhibitors include: (1) they act independent of insulin to lower plasma glucose therefore are not expected to be linked with hypoglycemia. (2) In hyperglycemia urinary glucose excretion (UGE) causes the increase of urinary caloric loss therefore increasing weight loss. Other classes of anti-hyperglycemia agents, which have shown to cause weight gain, but SGLT2 inhibitor is not expected to be associated with weight gain (Nomura, 2010). Canaglifoizin, is an SGLT2 inhibitor, being developed by Johnson & Jonson, and the aim of this paper is to review canaglifoizin for the treatment of T2DM. Method and Results: Discovery of Canaglifoizin In the 19th century, an O-glucoside phlorizin was discovered. It has a glucose half and an anglycone half, which are two aromatic rings that are brought together with an alkyl spacer. In 1886, phlorizin was shown to induce glycosuria (Nair, 2010). In 1980 the effects of phlorizin were tested in partly pancreatectomized rats, the results of experiment showed an increase in UGE linked with normal amount of plasma glucose and phlorizin did not induce hyperglycemia

Shakir 4 (Ehrenkranz, 2005). Phlorizin still has some flaws such as, phlorizin has a poor oral bioavailability because it is hydrolyzed to phloretin in the gut. Phlorizin also did not only target to in SGLT2 but it inhibited SGLT1 (Hardman, 2011). Since these finding of phlorizin there has been an ongoing search for a better, more effective SGLT2 inhibitor. Therefore various derivative based on the structure of phlorizin have been synthesized such as many o-glucosides and c-glucosides. A very important o-glucosides derivative, T-1095 was designed to be a SGLT2 inhibitor. T-1095 was orally administered to hyperglycemic high-fat diet fed KK (HF-KK). The pharmacodynamics results showed decreased hyperinsulinemia and hypertriglyceridemia. The results also indicated a decreased in insulin resistance (Oku, 2000). In another study, T-1095 was orally administered to streptozotocin-induced diabetic rats and Zucker diabetic fatty rats. Long term administration of T-1095 restored insulin secretion from the damaged β-cell in the pancreas. Although T-1095 showed to be an effective treatment of T2DM, in both types of mice with induced hyperglycemia and a high-fat diet, it was discontinued in 2003 because it inhibited SGLT1 along with SGLT2 (Hardman, 2011). Another derivative since the discontinuation of T-1095 has been synthesized, a thiophene derivative canagliflozin. Canagliflozin is a c-glucoside instead of the usual o-glucoside that was be being used. The difference between the c-glucoside and an o-glucoside is c-glucoside contain a heteroaromatic ring. In order to determine the stability of canagliflozin, first the inhibitory activity on SGLT1, SGLT2, and facilitated glucose transporter 1 (GLUT1) was tested. In order to conduct this test Sprague-Dawley (SD) rats were orally administered 30mg/kg of canagliflozin. The results of this experiment were, the half maximal inhibitor concentration (IC50 (nM)) for SGLT1 was 910nM, GLUT1 > 10000nM, and SGLT2 2.2nM. The urinary glucose

Shakir 5 excretion (UGE) tested for 24 hours was 3696mg/day. Second the pharmacokinetic (PK) in SD rats was determined after an oral and intravenous administration of canagliflozin. The rats were give a dose of 3mg/kg and 10mg/kg. The oral bioavailability was determined to be 85%.The result of a single oral administration of canagliflozin at 3mg/kg showed a reduction in blood glucose levels with an effect on food intake in hyperglycemic mice, on high fat diet KK (HFKK) mice. After 6 hours of the oral administration of canagliflozin the blood glucose level decreased by 48% in comparison to the vehicle. In the normoglycemic mice there was a slight effect on blood glucose levels (Nomura, 2010). Conclusion: The o-glucoside, phlorizin failed to have a good oral bioavailability and T-1095 failed to be selective for inhibiting only SGLT2, it was inhibiting SGLT1. But a c-glucoside, canaglifiozin is a very potent and selective inhibitor of SGLT2, according to half maximal inhibitor concentration (IC50 (nM)) value of 2.2nM and the most urinary glucose excretion, with 3696mg/day compared to the other compounds tested. It showed a reeducation in blood glucose levels without an influence on food intake and it only had a slight effect on the blood glucose levels of normoglycemic mice. Also according to the pharmacokinetic results, the oral bioavailability of cangliflozin was 85% (Nomura, 2010). Therefore, canagliflozin would be able to control hyperglycemia with low risk of hypoglycemia. Recently in January 2013, the U.S. Food and Drug Administration as approved the drug canagliflozin (common name Invokana) as a treatment of for T2DM (Clarke, 2013).

Shakir 6 References: 1. Centers of Disease Control and Prevention. (2011). Number of Americans with Diabetes Rises to Nearly 26 Million. Retrieved from 2. Clarke, Toni. "U.S. FDA Approves Johnson & Johnson Diabetes Drug, Canagliflozin." Reuters. Thomson Reuters, 27 Mar. 0029. Web. 19 Apr. 2013. 3. David Cooke and Leslie Plotnick Type 1 Diabetes Mellitus in Pediatrics, Pediatrics in Review, (2008), 29: 374-385. 4. Ehrenkranz RRL, Lewis NG, Kahn CR, Roth J. Phlorizin: a review. Diabetes Metab Res Rev., (2005), 21:31-38. 5. Oku A, Ueta K, Nawano M, et al. Antidiabetic effect of T-1095, an inhibitor of Na+glucose cotransporter, in neonatally streptozotocin-treated rats. European Journal of Pharmacology, (2000), 1-2;391:183-192. 6. Sumihiro Nomura, Shigeki Sakamaki, and Mitsuya Hongu 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, Journal of Medicinal Chemistry Article, (2010),53:6355-6360. 7. Timothy Hardman and Simon Dubrey, Development and Potential of Type-2 Sodium Glucose Tranporter Inhibitors for Management of Type 2 Diabetes, Diabetes Therapy, (2011), 2(3): 133-145.

Canaglifiozin, a SGLT2 Inhibitor