SGLT2 inhibitors: molecular design and potential differences in effect
2011; Elsevier BV; Volume: 79; Linguagem: Inglês
10.1038/ki.2010.511
ISSN1523-1755
Autores Tópico(s)Potassium and Related Disorders
ResumoThe physiological and pathological handling of glucose via sodium–glucose cotransporter-2 (SGLT2) in the kidneys has been evolving, and SGLT2 inhibitors have been focused upon as a novel drug for treating diabetes. SGLT2 inhibitors enhance renal glucose excretion by inhibiting renal glucose reabsorption. Consequently, SGLT2 inhibitors reduce plasma glucose insulin independently and improve insulin resistance in diabetes. To date, various SGLT2 inhibitors have been developed and evaluated in clinical studies. The potency and positioning of SGLT2 inhibitors as an antidiabetic drug are dependent on their characteristic profile, which induces selectivity, efficacy, pharmacokinetics, and safety. This profile decides which SGLT2 inhibitors can be expected for application of the theoretical concept of reducing renal glucose reabsorption for the treatment of diabetes. I review the structure and advancing profile of various SGLT2 inhibitors, comparing their similarities and differences, and discuss the expected SGLT2 inhibitors for an emerging category of antidiabetic drugs. The physiological and pathological handling of glucose via sodium–glucose cotransporter-2 (SGLT2) in the kidneys has been evolving, and SGLT2 inhibitors have been focused upon as a novel drug for treating diabetes. SGLT2 inhibitors enhance renal glucose excretion by inhibiting renal glucose reabsorption. Consequently, SGLT2 inhibitors reduce plasma glucose insulin independently and improve insulin resistance in diabetes. To date, various SGLT2 inhibitors have been developed and evaluated in clinical studies. The potency and positioning of SGLT2 inhibitors as an antidiabetic drug are dependent on their characteristic profile, which induces selectivity, efficacy, pharmacokinetics, and safety. This profile decides which SGLT2 inhibitors can be expected for application of the theoretical concept of reducing renal glucose reabsorption for the treatment of diabetes. I review the structure and advancing profile of various SGLT2 inhibitors, comparing their similarities and differences, and discuss the expected SGLT2 inhibitors for an emerging category of antidiabetic drugs. Hyperglycemia is a characteristic of diabetes and a big concern because of its association with increased risks of microvascular and macrovascular complications promoting cardiovascular diseases in diabetic patients. Type 1 and type 2 diabetes are characterized by an autoimmune disease and by impaired insulin secretion and insulin resistance, respectively. Type 2 diabetes has been increasing progressively in incidence with lifestyle changes and is now referred to as a metabolic disorder.1.Brunton S.A. The changing shape of type 2 diabetes.Medscape J Med. 2008; 10: 143PubMed Google Scholar,2.Hays N.P. Galassetti P.R. Coker R.H. Prevention and treatment of type 2 diabetes: current role of lifestyle, natural product, and pharmacological interventions.Pharmacol Ther. 2008; 118: 181-191Crossref PubMed Scopus (94) Google Scholar Basic management of type 2 diabetes consists of lifestyle interventions such as diet and exercise, which modulate the energy balance in a negative direction. Because of the insufficiency of maintaining proper lifestyle changes, various antidiabetic drugs have been used for reducing plasma glucose and improving insulin resistance.3.Nathan D.M. Buse J.B. Davidson M.B. et al.Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes.Diabetologia. 2006; 49: 1711-1721Crossref PubMed Scopus (401) Google Scholar When our goal of the treatment of diabetes is set on preventing the progression of diabetes itself and reducing its consequent complications, optimal glycemic control and tolerable safety become key points, as shown in large randomized clinical trials.4.Montori V.M. Fernandez-Balsells M. Glycemic control in type 2 diabetes: time for an evidence-based about-face?.Ann Intern Med. 2009; 150: 803-808Crossref PubMed Scopus (137) Google Scholar Therefore, a new strategy for achieving optimal glycemic control, resulting in lower HbA1c levels, has been expected for management of the diabetic patient. Here, modulation of renal glucose handling has been highlighted as a promising approach for improving hyperglycemia and insulin resistance without intolerable adverse effects.5.Abdul-Ghani M.A. DeFronzo R.A. Inhibition of renal glucose reabsorption: a novel strategy for achieving glucose control in type 2 diabetes mellitus.Endocr Pract. 2008; 14: 782-790Crossref PubMed Scopus (155) Google Scholar In the handling of renal glucose,6.Wright E.M. Loo D.D. Hirayama B.A. et al.Surprising versatility of Na+-glucose cotransporters: SLC5.Physiology (Bethesda). 2004; 19: 370-376Crossref PubMed Scopus (149) Google Scholar,7.Marsenic O. Glucose control by the kidney: an emerging target in diabetes.Am J Kidney Dis. 2009; 53: 875-883Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar the bulk of the filtered glucose is reabsorbed by the high-capacity low-affinity sodium–glucose cotransporter-2 (SGLT2),8.Kanai Y. Lee W.S. You G. et al.The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for d-glucose.J Clin Invest. 1994; 93: 397-404Crossref PubMed Scopus (538) Google Scholar which is a member of the solute carrier family 5A9.Isaji M. Sodium-glucose cotransporter inhibitors for diabetes.Curr Opin Investig Drugs. 2007; 8: 285-292PubMed Google Scholar and is distributed predominantly on the luminal surface of cells in the S1 segment of renal proximal tubules. The residual glucose is reabsorbed by the low-capacity high-affinity SGLT1 distributed in the S3 segment; SGLT4 may also participate in the reabsorption at least in part.10.Tazawa S. Yamato T. Fujikura H. et al.SLC5A9/SGLT4, a new Na+-dependent glucose transporter, is an essential transporter for mannose, 1,5-anhydro-d-glucitol, and fructose.Life Sci. 2005; 76: 1039-1050Crossref PubMed Scopus (143) Google Scholar SGLT2 inhibitors discard excess glucose into the urine by inhibiting renal glucose reabsorption, and may be referred to as a chemical inducer of familial renal glucosuria.11.Brodehl J. Oemar B.S. Hoyer P.F. Renal glucosuria.Pediatr Nephrol. 1987; 1: 502-508Crossref PubMed Scopus (29) Google Scholar,12.van den Heuvel L.P. Assink K. Willemsen M. et al.Autosomal recessive renal glucosuria attributable to a mutation in the sodium glucose cotransporter (SGLT2).Hum Genet. 2002; 111: 544-547Crossref PubMed Scopus (187) Google Scholar Consequently, they reduce the plasma glucose level and abolish glucose toxicity, resulting in improving the insulin resistance associated with diabetes.13.Jabbour S.A. Goldstein B.J. Sodium glucose co-transporter 2 inhibitors: blocking renal tubular reabsorption of glucose to improve glycaemic control in patients with diabetes.Int J Clin Pract. 2008; 62: 1279-1284Crossref PubMed Scopus (130) Google Scholar At present, many SGLT2 inhibitors are being used in late-phase clinical studies to confirm their potency and safety for the treatment of diabetes.14.Kipnes M. Dapagliflozin: an emerging treatment option in type 2 diabetes.Expert Opin Investig Drugs. 2009; 18: 327-334Crossref PubMed Scopus (15) Google Scholar In this review, the structure and advancing profile of various SGLT2 inhibitors are described, and the expected potential and positioning of SGLT2 inhibitors for an emerging category of antidiabetic drugs are discussed. Diverse structures of SGLT2 inhibitors have been disclosed in some papers and in a number of patents.9.Isaji M. Sodium-glucose cotransporter inhibitors for diabetes.Curr Opin Investig Drugs. 2007; 8: 285-292PubMed Google Scholar,15.Handlon A.L. Sodium glucose co-transporter 2 (SGLT2) inhibitors as potential antidiabetic agents.Expert Opin Ther Pat. 2005; 15: 1531-1540Crossref Scopus (46) Google Scholar Phlorizin, a β-d-glucoside, was the first non-selective SGLT inhibitor to be isolated from the root bark of the apple tree, and it consists of a glucose moiety and an aglycone in which two aromatic carbocycles are joined by an alkyl spacer (Figure 1a).16.Ehrenkranz J.R. Lewis N.G. Kahn C.R. et al.Phlorizin: a review.Diabetes Metab Res Rev. 2005; 21: 31-38Crossref PubMed Scopus (724) Google Scholar T-1095 is the prodrug of T-1095A, which is a non-selective SGLT inhibitor that is a derivative of phlorizin and categorized as an aromatic hydrocarbon O-glycoside (Figure 1b and c).17.Tsujihara K. Hongu M. Saito K. et al.Na(+)-glucose cotransporter (SGLT) inhibitors as antidiabetic agents. 4. Synthesis and pharmacological properties of 4′-dehydroxyphlorizin derivatives substituted on the B ring.J Med Chem. 1999; 42: 5311-5324Crossref PubMed Scopus (127) Google Scholar Thereafter, non-phlorizin O-glycoside derivatives inhibiting SGLT2 selectively were developed as the next generation. Sergliflozin, a prodrug of sergliflozin-A, is an aromatic O-glycoside (Figure 1d and e),18.Katsuno K. Fujimori Y. Takemura Y. et al.Sergliflozin, a novel selective inhibitor of low-affinity sodium glucose cotransporter (SGLT2), validates the critical role of SGLT2 in renal glucose reabsorption and modulates plasma glucose level.J Pharmacol Exp Ther. 2007; 320: 323-330Crossref PubMed Scopus (252) Google Scholar and remogliflozin etabonate, a prodrug of remogliflozin, is a heteroaromatic O-glycoside (Figure 1f and g).19.Fujimori Y. Katsuno K. Nakashima I. et al.Remogliflozin etabonate, in a novel category of selective low-affinity sodium glucose cotransporter (SGLT2) inhibitors, exhibits antidiabetic efficacy in rodent models.J Pharmacol Exp Ther. 2008; 327: 268-276Crossref PubMed Scopus (203) Google Scholar Furthermore, fused aromatic O-glycosides have also been developed.20.Zhang X. Urbanski M. Patel M. et al.Indole-glucosides as novel sodium glucose co-transporter 2 (SGLT2) inhibitors. Part 2.Bioorg Med Chem Lett. 2006; 16: 1696-1701Crossref PubMed Scopus (29) Google Scholar The next important structures are aromatic and heteroaromatic C-glycosides, in which the glucose moiety binds aglycone directly through a carbon–carbon bond.21.Link J.T. Sorensen B.K. A method for preparing C-glycosides related to phlorizin.Tetrahedron Lett. 2000; 41: 9213-9217Crossref Scopus (50) Google Scholar Dapagliflozin is a representative compound of aromatic C-glycosides (Figure 1h) for enhancing the chemical stability of the glycosidic bond.22.Meng W. Ellsworth B.A. Nirschl A.A. 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: 1145-1149Crossref PubMed Scopus (518) Google ScholarC-glycosides are more metabolically stable than O-glycosides because of their resistance to gastrointestinal β-glucosidases, and are rapidly absorbed in the gastrointestinal tract without modification of the prodrug form. Furthermore, N-glycosides, S-glycosides, and modified sugar rings have been developed for combination with various structures of aglycones. The structures of TA-7284, YM-543, ASP-1941, BI 10773, BI 44847, R-7201, TS-033, and TS-071 have not yet been disclosed. Clinical development stages of SGLT2 inhibitors are shown in Table 1. Brystol-Myers Squibb/AstraZeneca have been codeveloping dapagliflozin at the Phase III stage. Canagliflozin and ASP-1941 follow at the Phase III stage and BI 10773, BI 44847, R-7201, TS-071, and LX4211 are being developed at the Phase II stage. The first-generation compounds of each company have now been discontinued; namely, T-1095, sergliflozin, AVE2268, TS-033, and YM-543 have been abandoned and taken over by next-generation compounds. Recently, GlaxoSmithKline discontinued the development of remogliflozin etabonate.Table 1Clinical development of sodium–glucose cotransporter-2 (SGLT2) inhibitors for the treatment of diabetesDrugDevelopment companyPhase of developmentDapagliflozinBristol-Myers Squibb/AstraZenecaPhase IIICanagliflozinJNJ/Mitsubishi TanabePhase IIIASP-1941Astellas/KotobukiPhase III (Japan)BI 10773Boehringer IngelheimPhase IIBI 44847Boehringer Ingelheim/AjinomotoPhase IIR-7201Roche/ChugaiPhase IITS-071TaishoPhase IILX4211LexiconPhase IIRemogliflozinGlaxoSmithKlineDiscontinuedYM-543Astellas/KotobukiDiscontinuedTS-033TaishoDiscontinuedAVE2268Sanofi-AventisDiscontinuedSergliflozinGlaxoSmithKline/KisseiDiscontinuedT-1095TanabeDiscontinued Open table in a new tab Phlorizin was the first non-selective SGLT inhibitor; it induces glucose excretion into the urine, so-called Phlorizin-induced glucosuria, by suppressing the renal glucose reabsorption system.16.Ehrenkranz J.R. Lewis N.G. Kahn C.R. et al.Phlorizin: a review.Diabetes Metab Res Rev. 2005; 21: 31-38Crossref PubMed Scopus (724) Google Scholar Phlorizin lowers plasma glucose by enhancing renal glucose excretion independent of insulin secretion, and was used as a tool compound to demonstrate that hyperglycemia contributed to insulin resistance in diabetic animal models.23.Rossetti L. Smith D. Shulman G.I. et al.Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats.J Clin Invest. 1987; 79: 1510-1515Crossref PubMed Scopus (685) Google Scholar However, phlorizin is easily hydrolyzed by lactase-phlorizin hydrolase and poorly absorbed in the intestine, making it a difficult drug to develop for the treatment of diabetes. In addition, phloretin, the aglycone of phlorizin, was produced as a metabolite of phlorizin in vivo, and has the potency to uncouple mitochondrial oxidative phosphorylation and inhibit facilitative glucose transporter-1.16.Ehrenkranz J.R. Lewis N.G. Kahn C.R. et al.Phlorizin: a review.Diabetes Metab Res Rev. 2005; 21: 31-38Crossref PubMed Scopus (724) Google Scholar As mutations of glucose transporter-1 are associated with concerns about unwanted adverse effects,24.Seidner G. Alvarez M.G. Yeh J.I. et al.GLUT-1 deficiency syndrome caused by haploinsufficiency of the blood-brain barrier hexose carrier.Nat Genet. 1998; 18: 188-191Crossref PubMed Scopus (312) Google Scholar a more selective profile for SGLT is needed as the next generation. T-1095, a 4′-dehydroxyphlorizin derivative, was subsequently developed as the first orally absorbable non-selective SGLT inhibitor for overcoming the above disadvantage of phlorizin.17.Tsujihara K. Hongu M. Saito K. et al.Na(+)-glucose cotransporter (SGLT) inhibitors as antidiabetic agents. 4. Synthesis and pharmacological properties of 4′-dehydroxyphlorizin derivatives substituted on the B ring.J Med Chem. 1999; 42: 5311-5324Crossref PubMed Scopus (127) Google Scholar T-1095, the aglycone of which does not inhibit glucose transporter-1, is absorbed in the intestine and converted into an active form, T-1095A (IC50 values: 50 and 200 nmol/l toward human SGLT1 and human SGLT2, respectively). Studies on T-1095 revealed that this SGLT inhibitor decreased blood glucose and HbA1c levels, and ameliorated hyperinsulinemia and hypertriglyceridemia by enhancing renal glucose excretion by inhibiting renal glucose reabsorption.25.Oku A. Ueta K. Arakawa K. et al.T-1095, an inhibitor of renal Na+-glucose cotransporters, may provide a novel approach to treating diabetes.Diabetes. 1999; 48: 1794-1800Crossref PubMed Scopus (228) Google Scholar,26.Oku A. Ueta K. Arakawa K. et al.Correction of hyperglycemia and insulin sensitivity by T-1095, an inhibitor of renal Na+-glucose cotransporters, in streptozotocin-induced diabetic rats.Jpn J Pharmacol. 2000; 84: 351-354Crossref PubMed Scopus (23) Google Scholar In addition, T-1095 improved insulin resistance, consequently resulting in the recovery of both hepatic glucose production and glucose utilization rates.27.Oku A. Ueta K. Nawano M. et al.Antidiabetic effect of T-1095, an inhibitor of Na(+)-glucose cotransporter, in neonatally streptozotocin-treated rats.Eur J Pharmacol. 2000; 391: 183-192Crossref PubMed Scopus (59) Google Scholar,28.Nawano M. Oku A. Ueta K. et al.Hyperglycemia contributes insulin resistance in hepatic and adipose tissue but not skeletal muscle of ZDF rats.Am J Physiol Endocrinol Metab. 2000; 278: E535-E543PubMed Google Scholar Long-term administration of T-1095 restored the impaired insulin secretion from pancreatic β-cells and suppressed the development of diabetic complications.29.Fujimoto Y. Torres T.P. Donahue E.P. et al.Glucose toxicity is responsible for the development of impaired regulation of endogenous glucose production and hepatic glucokinase in Zucker diabetic fatty rats.Diabetes. 2006; 55: 2479-2490Crossref PubMed Scopus (39) Google Scholar, 30.Nunoi K. Yasuda K. Adachi T. et al.Beneficial effect of T-1095, a selective inhibitor of renal Na+-glucose cotransporters, on metabolic index and insulin secretion in spontaneously diabetic GK rats.Clin Exp Pharmacol Physiol. 2002; 29: 386-390Crossref PubMed Scopus (33) Google Scholar, 31.Arakawa K. Ishihara T. Oku A. et al.Improved diabetic syndrome in C57BL/KsJ-db/db mice by oral administration of the Na(+)-glucose cotransporter inhibitor T-1095.Br J Pharmacol. 2001; 132: 578-586Crossref PubMed Scopus (146) Google Scholar, 32.Ueta K. Ishihara T. Matsumoto Y. et al.Long-term treatment with the Na+-glucose cotransporter inhibitor T-1095 causes sustained improvement in hyperglycemia and prevents diabetic neuropathy in Goto-Kakizaki Rats.Life Sci. 2005; 76: 2655-2668Crossref PubMed Scopus (78) Google Scholar Treatment with T-1095 established that enhancing renal glucose excretion induced by inhibiting renal glucose reabsorption is effective for improving diabetic conditions. T-1095A inhibited both SGLT1 and SGLT2, and there is no consensus as to whether, for the treatment of type 2 diabetes, an SGLT1 inhibitory potency is needed in addition to SGLT2 inhibition. SGLT1 supports SGLT2 for glucose reabsorption in the kidney;6.Wright E.M. Loo D.D. Hirayama B.A. et al.Surprising versatility of Na+-glucose cotransporters: SLC5.Physiology (Bethesda). 2004; 19: 370-376Crossref PubMed Scopus (149) Google Scholar,7.Marsenic O. Glucose control by the kidney: an emerging target in diabetes.Am J Kidney Dis. 2009; 53: 875-883Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar therefore, use of SGLT1 inhibition in conjunction with inhibitory activity toward SGLT2 might result in a stronger potency than the use of a selective SGLT2 inhibitor alone. In addition, SGLT1 has an important role in glucose absorption in the intestines,6.Wright E.M. Loo D.D. Hirayama B.A. et al.Surprising versatility of Na+-glucose cotransporters: SLC5.Physiology (Bethesda). 2004; 19: 370-376Crossref PubMed Scopus (149) Google Scholar and SGLT1 inhibitors have been tried to be used for reducing glucose absorption in the intestines,9.Isaji M. Sodium-glucose cotransporter inhibitors for diabetes.Curr Opin Investig Drugs. 2007; 8: 285-292PubMed Google Scholar as have α-glucosidase inhibitors.33.Hanefeld M. Schaper F. Acarbose: oral anti-diabetes drug with additional cardiovascular benefits.Expert Rev Cardiovasc Ther. 2008; 6: 153-163Crossref PubMed Scopus (66) Google Scholar Upregulation of intestinal SGLT1 has been reported in diabetic patients.34.Debnam E.S. Smith M.W. Sharp P.A. et al.The effects of streptozotocin diabetes on sodium-glucose transporter (SGLT1) expression and function in rat jejunal and ileal villus-attached enterocytes.Pflugers Arch. 1995; 430: 151-159Crossref PubMed Scopus (40) Google Scholar If SGLT1 inhibitors could suppress just a portion of this upregulated SGLT1 activity, it could exert beneficial effects on diabetes without affecting physiological glucose absorption by SGLT1. However, a worrisome adverse effect is the induction of gastrointestinal disturbances as seen in patients treated with α-glucosidase inhibitors and in glucose–galactose malabsorption patients with mutations of SGLT1.35.Turk E. Zabel B. Mundlos S. et al.Glucose/galactose malabsorption caused by a defect in the Na+/glucose cotransporter.Nature. 1991; 350: 354-356Crossref PubMed Scopus (314) Google Scholar SGLT1 is known to be expressed in human cardiomyocytes, and it is an open question as to what kind of functional consequences might result from SGLT1 inhibition in the heart.36.Zhou L. Cryan E.V. D'Andrea M.R. et al.Human cardiomyocytes express high level of Na+/glucose cotransporter 1 (SGLT1).J Cell Biochem. 2003; 90: 339-346Crossref PubMed Scopus (160) Google Scholar Indeed, in patients with glucose–galactose malabsorption caused by mutation of SGLT1, cardiomyopathy has not been a concern.35.Turk E. Zabel B. Mundlos S. et al.Glucose/galactose malabsorption caused by a defect in the Na+/glucose cotransporter.Nature. 1991; 350: 354-356Crossref PubMed Scopus (314) Google Scholar The necessity for inhibiting SGLT1 activity concomitantly with SGLT2 inhibition may be an issue as to the balance between advantages and disadvantages, and thus further information will be needed to control the balance optimally. Nevertheless, it may be reasonable to develop more selective SGLT2 inhibitors imitating the condition of familial renal glucosuria without gastrointestinal adverse effects and cardiovascular risk compared with those available at present. WAY-123783 was expected to be a candidate of a non-glycoside SGLT2 inhibitor, a new class of antidiabetic agent, to improve hyperglycemia. Because O-glycosides are unstable in the gastrointestinal tracts, non-glycoside inhibitors are expected to overcome the unstable nature of glycoside inhibitors. WAY-123783 induced glucosuria in normal mice and is considered to suppress renal glucose reabsorption by affecting SGLT2 function.37.Kees K.L. Fitzgerald Jr, J.J. Steiner K.E. et al.New potent antihyperglycemic agents in db/db mice: synthesis and structure-activity relationship studies of (4-substituted benzyl) (trifluoromethyl)pyrazoles and -pyrazolones.J Med Chem. 1996; 39: 3920-3928Crossref PubMed Scopus (309) Google Scholar However, WAY-123783 was unable to inhibit SGLT activity in vitro or to induce glucosuria in rats.17.Tsujihara K. Hongu M. Saito K. et al.Na(+)-glucose cotransporter (SGLT) inhibitors as antidiabetic agents. 4. Synthesis and pharmacological properties of 4′-dehydroxyphlorizin derivatives substituted on the B ring.J Med Chem. 1999; 42: 5311-5324Crossref PubMed Scopus (127) Google Scholar,38.Ohsumi K. Matsueda H. Hatanaka T. et al.Pyrazole-O-glucosides as novel Na(+)-glucose cotransporter (SGLT) inhibitors.Bioorg Med Chem Lett. 2003; 13: 2269-2272Crossref PubMed Scopus (52) Google Scholar As to the mechanism, WAY-123783 was shown to be converted to WAY-123783-glycoside in only mice, with this active metabolite inhibiting SGLT activity.38.Ohsumi K. Matsueda H. Hatanaka T. et al.Pyrazole-O-glucosides as novel Na(+)-glucose cotransporter (SGLT) inhibitors.Bioorg Med Chem Lett. 2003; 13: 2269-2272Crossref PubMed Scopus (52) Google Scholar On the basis of this finding, WAY-123783-glycoside has been referred to as an SGLT2 inhibitor. Currently, almost all SGLT2 inhibitors are in the glycosides category, and no non-glycoside inhibitors have been developed for clinical use. Eventually, altered glucose moiety structures may be needed for the designing of SGLT2 inhibitors, and SGLT2 may strictly recognize such glucose structures. Sergliflozin was then developed as a selective SGLT2 inhibitor.18.Katsuno K. Fujimori Y. Takemura Y. et al.Sergliflozin, a novel selective inhibitor of low-affinity sodium glucose cotransporter (SGLT2), validates the critical role of SGLT2 in renal glucose reabsorption and modulates plasma glucose level.J Pharmacol Exp Ther. 2007; 320: 323-330Crossref PubMed Scopus (252) Google Scholar On the basis of calculated Ki values, sergliflozin-A, the active form of sergliflozin, is 296-fold more selective for SGLT2 than for SGLT1 (Ki values: 2.39 and 708 nmol/l toward human SGLT2 and human SGLT1, respectively) without affecting glucose transporter-1 activity. This selective SGLT2 inhibitor validated the idea that SGLT2 has a key role in renal glucose reabsorption, and consequently improves hyperglycemia as well as did T-1095.18.Katsuno K. Fujimori Y. Takemura Y. et al.Sergliflozin, a novel selective inhibitor of low-affinity sodium glucose cotransporter (SGLT2), validates the critical role of SGLT2 in renal glucose reabsorption and modulates plasma glucose level.J Pharmacol Exp Ther. 2007; 320: 323-330Crossref PubMed Scopus (252) Google Scholar,39.Fujimori Y. Katsuno K. Ojima K. et al.Sergliflozin etabonate, a selective SGLT2 inhibitor, improves glycemic control in streptozotocin-induced diabetic rats and Zucker fatty rats.Eur J Pharmacol. 2009; 609: 148-154Crossref PubMed Scopus (66) Google Scholar In addition, sergliflozin did not exert hypoglycemia and SGLT1-dependent induction of gastrointestinal adverse effects even when given as a 1000-mg dose three times daily in a Phase I study;40.Hussey E.K. Dobbins R.I. Stolz R.R. et al.A double-blind randomized repeat dose to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of three times daily dosing of sergliflozin, a novel inhibitor of renal glucose reabsorption, in healthy overweight and obese subjects [0491-P].Diabetes. 2007; 56: A491Google Scholar further, the selectivity of sergliflozin for SGLT1 was low enough for it to be a candidate for clinical treatment. Interestingly, treatment with sergliflozin increased mean plasma glucagon-like peptide-1 levels in that study. It is known that glucagon-like peptide-1 is secreted from intestinal L-cells in response to a meal or glucose stimulus.41.Stonehouse A.H. Holcombe J.H. Kendall D.M. Management of Type 2 diabetes: the role of incretin mimetics.Expert Opin Pharmacother. 2006; 7: 2095-2105Crossref PubMed Scopus (27) Google Scholar A hypothesis may be proposed that sergliflozin inhibited optimal glucose absorption in the upper intestinal tract, and then the non-absorbed glucose moved toward the lower intestinal tract, where it consequently stimulated the glucagon-like peptide-1 secretion from L-cells. If so, sergliflozin may have optimal SGLT1 inhibitory activity to allow secretion of glucagon-like peptide-1 without inducing gastrointestinal disturbance. Remogliflozin etabonate was developed as a follow-on compound of sergliflozin to advance the selectivity and pharmacokinetic (PK) profile of SGLT2 inhibitors.19.Fujimori Y. Katsuno K. Nakashima I. et al.Remogliflozin etabonate, in a novel category of selective low-affinity sodium glucose cotransporter (SGLT2) inhibitors, exhibits antidiabetic efficacy in rodent models.J Pharmacol Exp Ther. 2008; 327: 268-276Crossref PubMed Scopus (203) Google Scholar Remogliflozin etabonate is an O-glycoside structure, and is converted into its active form, remogliflozin, in the body. Remogliflozin has higher selectivity (Ki values: 12.4 and 4520 nmol/l toward human SGLT2 and human SGLT1, respectively), and remogliflozin etabonate has stronger potency toward inhibition of SGLT2 in vivo than have Phlorizin, T-1095, and sergliflozin. Although remogliflozin etabonate is an O-glycoside susceptible to β-glucosidase, the PK profile and potency of remogliflozin etabonate may have been advanced. Indeed, renal excretion of glucose in response to remogliflozin etabonate given as a 50-mg dose twice daily to type 2 diabetic patients was ∼70 g/day,42.Kapur A. O'Connor-Semmes R. Hussey E. et al.First human dose-escalation study with remogliflozin etabonate (RE) in healthy subjects and in subjects with type 2 diabetes mellitus (T2DM) [509-P].Diabetes. 2009; 58: A136Google Scholar which was similar to that of dapagliflozin given as a 25-mg dose once daily in a 2-week study.43.Komoroski B. Vachharajani N. Feng Y. et al.Dapagliflozin, a novel, selective SGLT2 inhibitor, improved glycemic control over 2 weeks in patients with type 2 diabetes mellitus.Clin Pharmacol Ther. 2009; 85: 513-519Crossref PubMed Scopus (339) Google Scholar Furthermore, remogliflozin etabonate caused a decrease in not only hyperglycemic parameters and body weight but also blood pressure.44.Dobbins R. Kapur A. Kapitza C. et al.Remogliflozin etabonate, a selective inhibitor of the sodium-glucose transporter 2 (SGLT2) reduces serum glucose in type 2 diabetes mellitus (T2DM) patients [573-P].Diabetes. 2009; 58: A154Google Scholar Dapagliflozin is a more selective and stronger SGLT2 inhibitor (EC50 values: 1.12 and 1391 nmol/l toward human SGLT2 and human SGLT1, respectively) than remogliflozin and is a representative compound of SGLT2 inhibitors with a C-glycoside structure, which is a recent major category of SGLT2 inhibitors, and the first runner of SGLT2 development for clinical use.22.Meng W. Ellsworth B.A. Nirschl A.A. 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: 1145-1149Crossref PubMed Scopus (518) Google Scholar,45.Han S. Hagan D.L. Taylor J.R. et al.Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats.Diabetes. 2008; 57: 1723-1729Crossref PubMed Scopus (351) Google Scholar These C-arylglycosides are easily absorbed without modifying the prodrug form and have a long-acting PK profile because of their greater resistance to β-glucosidase than to O-glycosides. In a 2-week study,43.Komoroski B. Vachharajani N. Feng Y. et al.Dapagliflozin, a novel, selective SGLT2 inhibitor, improved glycemic control over 2 weeks in patients with type 2 diabetes mellitus.Clin Pharmacol Ther. 2009; 85: 513-519Crossref PubMed Scopus (339) Google Scholar the terminal elimination half-life (T1/2) of dapagliflozin was ∼16 h in the fasted state, and once-daily dosing has been enough to reveal their efficacy. Dapagliflozin-induced renal glucose excretion on day 14 in patients with established type 2 diabetes was 36.6, 70.1, and 69.9 g/day at daily doses of 5, 25, and 100 mg, respectively. Fasting plasma glucose was reduced in a dose-dependent manner, and significant improvement in the results of the oral glucose tolerance test was also observed. In once-daily dosing in a 12-week study,46.List J.F. Woo V. Morales E. et al.Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes.Diabetes Care. 2009; 32: 650-657Crossref PubMed Scopus (572) Google Scholar excreted renal glucose was 52–85 g/day at 2.5–50 mg doses of dapagliflozin; dapagliflozin improved diabetic parameters, for example, by causing a significant decrease in HbA1c and fasting plasma glucose. Furthermore, dapagliflozin treatment led to decreases in body weight and serum uric acid, had a tendency to reduce blood pressure, and may also have therapeutic potential for the treatment of metabolic syndrome. However, for a long-term medication regimen, a dose-dependent increase in urine volume and hematocrit in a dose-dependent manner should be of concern, as well as urinary tract and genital tract infections seen in 5–12% (6% of placebo-treated patients) and 2–7% (0 % of placebo-treated patients), respectively, of dapagliflozin-treated patients. New SGLT2 inhibitors have been developed by modifying the prototypic phlorizin, and now efforts are advancing and aiming for the best possible inhibitors.47.Bays H. From victim to ally: the kidney as an emerging target for the treatment of diabetes mellitus.Curr Med Res Opin. 2009; 25: 671-681Crossref PubMed Scopus (75) Google Scholar Recently, following the discontinuation of the non-selective SGLT inhibitors T-1095 and TS-033, even SGLT2-selective inhibitors such as sergliflozin, AVE2248, and YM-743 have also been discontinued. Many companies have exchanged their first candidates for follow-on compounds after the conclusion of proof-of-concept Phase II studies. Sergliflozin and AVE2248 (IC50 values: 11 and >10,000 nmol/l toward human SGLT2 and human SGLT1, respectively, for AVE2248)48.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: 574-580PubMed Google Scholar have improved the disadvantages of phlorizin and T-1095, and increased the selectivity of SGLT2 without inducing gastrointestinal adverse effects dependent on the inhibition of SGLT1. Interestingly, remogliflozin etabonate and dapagliflozin had a tendency to reduce blood pressure in a clinical study by osmotic diuretic effects and probably by effects on the tubuloglomerular reflex.44.Dobbins R. Kapur A. Kapitza C. et al.Remogliflozin etabonate, a selective inhibitor of the sodium-glucose transporter 2 (SGLT2) reduces serum glucose in type 2 diabetes mellitus (T2DM) patients [573-P].Diabetes. 2009; 58: A154Google Scholar, 46.List J.F. Woo V. Morales E. et al.Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes.Diabetes Care. 2009; 32: 650-657Crossref PubMed Scopus (572) Google Scholar, 49.Schnermann J. Juxtaglomerular cell complex in the regulation of renal salt excretion.Am J Physiol. 1998; 274: R263-R279PubMed Google Scholar SGLT2 has a larger capacity for Na+ reabsorption than SGLT1 in proportion to the larger capacity of glucose reabsorption of SGLT2, and SGLT1 has a stronger potential to reabsorb Na+ and water than SGLT2. In the case of inhibition of SGLT2, SGLT1 must work at full capacity to reabsorb not only glucose but also Na+ and water, which were not absorbed by SGLT2 distributed upstream of the SGLT1 location.5.Abdul-Ghani M.A. DeFronzo R.A. Inhibition of renal glucose reabsorption: a novel strategy for achieving glucose control in type 2 diabetes mellitus.Endocr Pract. 2008; 14: 782-790Crossref PubMed Scopus (155) Google Scholar, 8.Kanai Y. Lee W.S. You G. et al.The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for d-glucose.J Clin Invest. 1994; 93: 397-404Crossref PubMed Scopus (538) Google Scholar, 47.Bays H. From victim to ally: the kidney as an emerging target for the treatment of diabetes mellitus.Curr Med Res Opin. 2009; 25: 671-681Crossref PubMed Scopus (75) Google Scholar In Xenopus laveis oocytes expressing SGLT1, water is transported by three mechanisms, that is, by Na+-glucose-water cotransport (35%), osmosis through SGLT1 (35%), and osmotic diffusion (30%).6.Wright E.M. Loo D.D. Hirayama B.A. et al.Surprising versatility of Na+-glucose cotransporters: SLC5.Physiology (Bethesda). 2004; 19: 370-376Crossref PubMed Scopus (149) Google Scholar It would be interesting to assess whether SGLT2 inhibitors with or without SGLT1 inhibition would affect the tubuloglomerular feedback reflex, and to what degree polyuria would be induced and blood pressure changed. However, peak of delivery into the circulation and homeostatic mechanisms for both Na+ and water do not always correspond to those of glucose,6.Wright E.M. Loo D.D. Hirayama B.A. et al.Surprising versatility of Na+-glucose cotransporters: SLC5.Physiology (Bethesda). 2004; 19: 370-376Crossref PubMed Scopus (149) Google Scholar,50.Thomson S.C. Blantz R.C. Glomerulotubular balance, tubuloglomerular feedback, and salt homeostasis.J Am Soc Nephrol. 2008; 19: 2272-2275Crossref PubMed Scopus (73) Google Scholar and therefore the PK profile of inhibitors in terms of modulating Na+ and water handling concomitant with the glucose handling might affect the incidence and degree of unfavorable reactions such as electrolyte imbalance and polyuria. From the point of view of the PK profile, C-glycosides such as dapagliflozin have a profile for longer-acting renal glucose excretion than O-glycosides. The long-acting C-glycoside SGLT2 inhibitor can suppress both postprandial and fasting hyperglycemia during daytime and night time by dosing once daily. On the other hand, the short-acting O-glycoside SGLT2 inhibitor such as sergliflozin can limitedly affect the targeting phase such as the postprandial hyperglycemia in which plasma glucose profile almost corresponds with their PK profile. Improving postprandial hyperglycemia is very important for preventing the progress of atherosclerosis and cardiovascular events.51.Leiter L.A. Ceriello A. Davidson J.A. et al.Postprandial glucose regulation: new data and new implications.Clin Ther. 2005; 27: S42-S46Abstract Full Text PDF PubMed Scopus (147) Google Scholar Modulation of fasting glucose levels, which may improve impaired insulin sensitivity, is important for strict glycemic control.52.Herman M.A. Kahn B.B. Glucose transport and sensing in the maintenance of glucose homeostasis and metabolic harmony.J Clin Invest. 2006; 116: 1767-1775Crossref PubMed Scopus (266) Google ScholarC-glycosides are suitable for pursuing stronger potency because of continuing glucose excretion during daytime and night time by daily dosing once, which is superior to the short-acting O-glycosides for compliance in drug taking. On the contrary, O-glycosides are reasonable for a better safety profile because of targeting just the postprandial phase, in which delivery of exogenous glucose, electrolytes, and water into circulation is greater than during the fasting phase. At present, many pharmaceutical companies have been pursuing, first of all, SGLT2 selective compounds with longer acting and stronger potency. In the near future, long-term clinical studies will reveal the ideal profile of SGLT2 inhibitors, comprising selectivity, efficacy, PK profile, safety, and benefits of combination therapy with other antidiabetic drugs. There is considerable interest in the extent to which SGLT2 inhibitors promote excretion of renal glucose and reduce HbA1c levels, whether the combination therapy with other antidiabetic drugs amplifies the potency or adverse effects, how long they medicate without inducing intolerable adverse effects, and to what extent they prevent the progress of complications. The stage is now set to confirm the real potency and optimal positioning of SGLT2 inhibitors as a novel category of antidiabetic drugs. Currently, many companies are developing various SGLT2 inhibitors having characteristic profiles that differ in terms of structure, selectivity, efficacy, PKs, and safety. Long-term clinical studies have been conducted to reveal the ideal profile of SGLT2 inhibitors. SGLT2 inhibitors are referred to as a chemical inducer of familial renal glucosuria and as an energy controller acting in the negative direction, alongside lifestyle interventions. On the basis of this principle, SGLT2 inhibitors are expected to achieve long-term glycemic control, improve insulin resistance, and preserve pancreatic β-cell function without inducing body weight gain or increasing hypoglycemic risk. The therapeutic potency, safety, and tolerability of SGLT2 may be beneficial for the treatment of diabetes, and it may be expected to display synergistic effects when used in combination with multiple antidiabetic drugs. In the near future, positioning SGLT2 inhibitors as antidiabetic drugs will be firmly established.
Referência(s)