Main types of current therapeutic agents for T2DM and their major side effects (Israili, 2011; Moller, 2001)
1. Introduction
Diabetes mellitus is characterized by chronically elevated serum glucose levels resulting in damage of several tissues (e. g. retina, kidney, nerves) due to higher protein glycation, retardation of wound healing, impaired insulin secretion, enhanced insulin resistance, cell apoptosis, and increased oxidative stress. Type 2 diabetes (T2DM), representing 90-95 % of all diabetic cases, is a multifactorial disease where impaired insulin secretion and the development of insulin resistance ultimately leads to hyperglycemia (Hengesh, 1995). The end of the 20th century has witnessed a dramatic increase in the number of patients diagnosed with diabetes worldwide. The predicted number for the year 2025 is well over 300 million representing a 4-5 % yearly increase of the population above 20 years of age (Treadway et al., 2001). This striking prevalence can even be an underestimate due to methodological uncertainties as well as undiagnosed cases (Green et al., 2003). The highest increases are expected in the developing countries of Africa, Asia, and South America, while European populations seem to be less affected (Diamond, 2003). T2DM has been considered as the adult- or late-onset variant, however, the recent decade has seen the appearance and spreading of the disease among young people including children: this forecasts severe economic and health service burdens in the near future (Alberti et al., 2004; Ehtisham & Barrett, 2004).
The epidemic of T2DM is in conjunction with genetic susceptibility: evidence for a genetic component to the disease are accumulating, and the potential of these factors in the treatment and prevention of diabetes has been reviewed (Barroso, 2005; Bonnefond et al., 2010; Sladek et al., 2007; Toye & Gauguier, 2003). A similarly high contribution to this epidemic may originate from behavioral factors such as sedentary lifestyle, overly rich nutrition, and obesity (Bloomgarden, 2004).
Especially due to its long term complications (Brownlee, 2001) like retinopathy, neuropathy, nephropathy, and in particular cardiovascular diseases, as well as significantly higher risk of myocardial infarction, stroke, gangrene, and limb amputation diabetes has become one of the largest contributors to disability and mortality. Although several pathomechanisms (Lowell & Shulman, 2005; Panunti et al., 2004; Stumvoll et al., 2005) are under investigation, no firm understanding of the molecular origins (Ross et al., 2004) of the disease exists. Thereby, all available and investigational treatments are symptomatic. As the complications can first of all be attributed to the high blood glucose levels, current antidiabetic therapies (Table 1) aim at reaching normoglycemia. However, most of the applied oral hypoglycemic agents (Cheng & Fantus, 2005; Krentz & Bailey, 2005; Mizuno et al., 2008; Padwal et al., 2005; Rendell, 2004; Uwaifo & Ratner, 2005) have several side effects and are inadequate for 30-40 % of the patients (Wagman & Nuss, 2001). On the other hand, their efficacy is lost over the time, and several concerns exist regarding their safety (Israili, 2011).
Drug type | Molecular target | Site of action | Adverse effects |
Insulin sensitizers | |||
Metformin (biguanides) |
Unknown | Liver, intestine, pancreas | Gastrointestinal intolerance (diarrhea, nausea), lactic acidosis, decreased vitamin B12 level |
Thiazolidinediones (glitazones) | PPARγ | Liver, adipose tissue, skeletal muscle | Weight gain, ankle edema, sodium and fluid retention, possible bone loss |
Insulin secretagogues | |||
Sulfonylureas |
Sulfonylurea receptor | Pancreas | Weight gain, hypoglycemia, hyperinsulinemia, hypoglycemia-provoked ischemia and arrhythmia, progressive decline in β-cell function |
Meglitinides | K-ATP channel | Pancreas | Weight gain, hypoglycemia, hypoglycemia-provoked ischemia and arrhythmia |
GLP-1 analogues and mimetics | GLP-1 receptor | Pancreas | Nausea, vomiting, diarrhea |
DPP-4 inhibitors (glinides) | DPP-4 | Intestine, pancreas | Gastrointestinal intolerance, nasopharyngitis, upper respiratory infection, urinary tract infection |
Others | |||
α-Glucosidase inhibitors | α-Glucosidases | Pancreas, small intestine | Gastrointestinal intolerance (flatulence, bloating) |
SGLT2-inhibitors (gliflozins) | SGLT2 | Kidney | Gastrointestinal intolerance (nausea), urinary tract infection |
Insulin | Insulin receptor | Liver, muscles | Weight gain, hypoglycemia |
The complexity of T2DM offers many potential points of intervention for pharmacotherapy for which the main molecular targets and strategies such as insulin secretagogues, insulin sensitizers, hormones, inhibitors of PTP-1B, GSK3, and hepatic glucose production, methods for altering lipid metabolism, combination therapies, etc. have been reviewed in details (Israili, 2011; Morral, 2003; Nourparvar et al., 2004; Wagman et al., 2004).
Among the numerous methods used to treat type 2 diabetes and investigated to find new therapeutic possibilities there are several approaches which apply carbohydrate (especially glucose) derivatives as well as compounds mimicking the properties of sugars. Based on our experience in the chemistry of carbohydrates and glycomimetics, in this survey we summarize the roles of such compounds in combatting type 2 diabetes relying on the review literature and very recent primary scientific papers.
2. Inhibitors of α-glucosidase enzymes
Starch and sucrose are the most important dietary carbohydrates but they are not directly available for the cells. They are digested in the gastrointestinal tract to monosaccharides which can be absorbed to the circulation to raise the serum concentration (Hanhineva et al., 2010). The normal blood glucose level (3.6–5.8 mM) fluctuates throughout the day, is usually lowest in the morning, before the first meal of the day, and rises after meals for an hour or two.
A medically applied treatment of diabetes is to retard the absorption of glucose by inhibition of the carbohydrate hydrolyzing enzymes α-amylase and α-glucosidase in the digestive tract. In humans the digestion of starch, maltodextrins, and maltooligosaccharides includes several stages: degradation of the polymeric substrates results in shorter oligomers which are than cleaved by α-amylase into smaller oligosaccharides. This mixture is broken down to monosaccharides by α-glucosidase from the non-reducing end of the oligosaccharides. By inhibition of these enzymes the rate of glucose production can be reduced that contributes to diminishing the blood glucose levels, too (Tundis et al., 2010). Such inhibitors decrease postprandial hyperglycaemia and hyperinsulinaemia, thereby may improve sensitivity to insulin and release the stress on β-cells (Scheen, 2003).
Glycosidases are a long known and studied class of glycoenzymes for which an enormous number of compounds have been tested as inhibitors (El Ashry et al., 2000a; El Ashry et al., 2000b; El Ashry et al., 2000c; Lillelund et al., 2002). Analogues of monosaccharides in which the ring oxygen is replaced by a nitrogen atom are known as iminosugars (or less properly azasugars) comprising both natural and synthetic molecules (Table 2) which, as the most potent inhibitors of glycosidases, have high pharmacological potential not only in the context of T2DM (Asano, 2009; Compain & Martin, 2007).
The naturally occurring salacinol and analogous sugar mimics with a 4-thiofuranoid type ring (Table 2) belong to a growing class of zwitterionic glycosidase inhibitors, which attract great interest both as synthetic targets and applications for α-glucosidase inhibition (Praly & Vidal, 2010).
The positive charge on the sulfur atom in the thiosugar derivatives and in the iminosugar-based glycosidase inhibitors at physiological pH is facilitating the binding in the active sites of glycosidase enzymes as a mimicry of the charge of the oxocarbeniumion-like transition state formed during hydrolysis of the natural enzyme substrate (Zechel & Withers, 2000). The stabilizing electrostatic interactions between the ammonium (protonated nitrogen) or sulfonium (positively charged sulfur) moieties and an active-site carboxylate residue are considered to be a possible mechanism of action of these inhibitors (Mohan & Pinto, 2007).
Three competitive inhibitors of α-glucosidases: acarbose, miglitol, and voglibose (de Melo et al., 2006) (Table 3) are used as drugs in the treatment of T2DM under various brand names. These compounds are known to inhibit a wide range of glycosidases. In the absence of specificity and because of the known serious side effects, the applications of these first generation iminosugar drugs are limited. Current investigations aim at discovering safer, more specific, and effective iminosugar based derivatives not only as hypoglycemic agents but for several other purposes among others in oncology, as antivirals, and against cystic fibrosis as reviewed in (Home et al., 2011).
|
Select iminosugar and thiosugar type inhibitors and their effect againstα-glucosidases originating from mammalian gastrointestinal tract
Name | Structure | Side-effect |
Acarbose Approved in 1995 |
|
Flatulence (78% of the patients) Diarrhea (14% of the patients) |
Miglitol Approved in 1996 |
|
Diarrhea, gas, soft stools, stomach pain |
Voglibose Approved in 1997 |
|
Diarrhea, stool loss, meteorism, upset stomach |
3. Inhibitors of renal sodium-glucose cotransporters
The mammalian kidney plays an important role in the maintenance of energy balance of the organism. In healthy individuals 180 g/day of D-glucose is filtered from plasma through the glomerulus, which is completely reabsorbed in the renal proximal tubules to the blood-stream, thereby preventing the loss of glucose in the urine (Wright, 2001). This reabsorption process is mediated by two sodium dependent glucose cotransporters (SGLTs). SGLT1 is a high-affinity, low-capacity glucose/galactose transporter located predominantly in the small intestine, but is also present in the S3 segment of the proximal tubule in the kidney, as well as in the heart. The primary function of SGLT1 is the absorbtion of dietary glucose in the intestine, however it shares in the renal glucose transport in the kidney and regulates cardiac glucose transport in the heart, as well. SGLT2 is a low affinity, high capacity glucose transporter specifically expressed in the S1 segment of the proximal convoluted tubule. SGLT2 is responsible for ~90 % of renal glucose reabsorption, while SGLT1 plays only an auxiliary role in this process (Boldys & Okopien, 2009; Idris & Donnelly, 2009; Washburn, 2009b). Genetic studies demonstrated that defects of SGLT2 but in a lesser extent of SGLT1 genes had neither adverse effects on kidney function as well as carbohydrate metabolism, nor hypoglycaemia (Handlon, 2005; Santer & Calado, 2010; Wright, 2001).
Nowadays sodium-glucose cotransporters have received remarkable attention as new drug targets for the treatment of diabetes (Bailey, 2011). Considering the exclusive expression of SGLT2 in the kidney and its predominant role in renal glucose recovery, most pharmaceutical investigations have focused primarily on selective SGLT2 inhibition to facilitate benign glucosuria (Santer & Calado, 2010; Washburn, 2009b). In contrast to the currently applied diabetic therapies most of which aim at insulin resistance and insulin deficiency, targeting SGLT2 is an insulin-independent strategy based on enhanced renal glucose excretion and, consequently, lowering plasma glucose levels without severe side effects (Isaji, 2007).
In recent years aromatic, heteroaromatic, and fused aromatic
R = H unless indicated otherwise |
|||||
Entry | R’ | Entry | R’ | Entry | R’ |
1. |
|
2. |
|
3. |
|
Phlorizin 35.6* (Meng et al., 2008) 18.6** (Katsuno et al., 2007) |
T-1095 R = COOMe (prodrug form) T-1095A R = H (active form) 50 (Handlon, 2005) 6.6* (Meng et al., 2008) |
Sergliflozin R = COOEt (prodrug form) Sergliflozin-A R = H (active form) 9.2* (Meng et al., 2008) 2.39** (Katsuno et al., 2007) |
|||
4. |
|
5. |
|
6. |
|
0.1 (Handlon, 2005) | Remogliflozin etabonate R = COOEt (prodrug form) Remogliflozin R = H (active form) 12.4** (Fujimori et al., 2008) |
BI 44847 (Washburn, 2009b) | |||
7. |
|
8. |
|
9. |
|
3 (Handlon, 2005) | 8 (Handlon, 2005) | 20 (Handlon, 2005) |
The first class of potential SGLT2 inhibitors to be explored was the
T-1095 (Table 4, Entry 2) is a methyl carbonate prodrug which, after oral administration, is rapidly converted to an active metabolite, T-1095A showing high affinity and plausible selectivity against human SGLT2 (Handlon, 2005). Development of T-1095 reached phase II clinical trials but was subsequently discontinued (Isaji, 2007).
The β-D-glucosides in which the aglycone moiety is a phenyl ring substituted in ortho position by a benzyl group represent a promising type of
Heteroaromatic
Efficacy of a series of benzofused heterocyclic derivatives was also investigated and, for example, benzotriazole and indole
Susceptibility of
Compounds containing a diarylmethane aglycone represent the first type of this class (Table 5). According to the SAR the benzyl substituent in meta position of the central aryl ring is more favourable compared to the ortho attached derivatives of high activity in case of
Additional SAR exploration revealed that introduction of an appropriate ortho substituent at the proximal phenyl ring adjacent to the glycosidic bond is beneficial in respect of inhibitory efficiency (Entry 2) (Washburn, 2009a). For example, propargyl ether derivative (Entry 3) exhibited sub-nanomolar activity and a more than 3300-fold selectivity for SGLT2 (Xu et al., 2010).
Replacement of the distal phenyl group with fused rings resulted in a new potent inhibitor type. For example, 1:1 choline complex of azulene (Entry 4) as well as 1:1 L-proline complex of benzothiophene (Entry 5) derivatives appeared as clinical candidates (Washburn, 2009b).
Modification of dapagliflozin by replacing the distal aryl ring by heterocycles led to the discovery of canagliflozin (Entry 6) which obtained the second highest interest in clinical developments ( Nomura et al., 2010 ).
Recently, along this line, the structure of dapagliflozin was modified by other heterocycles such as thiazole (Song et al., 2011), 1,3,4-thiadiazole (Lee et al., 2010b), pyridazine (Kim et al., 2010), and pyrimidine (Lee et al., 2010a) moieties. Among them, the thiazole derivative
|
|||||
Entry | R | Entry | R | Entry | R |
1. |
|
2. |
|
3. |
|
Dapagliflozin BMS-512148 1.1* (Meng et al., 2008) 0.49 (Song et al., 2011) 6.7 (Xu et al., 2010) 1.4 (Robinson et al., 2010) |
1.3* (Nomura, 2010) | 0.3 (Xu et al., 2010) | |||
4. |
|
5. |
|
6. |
|
YM-543 = 1:1 complexwith choline 8.9 (Washburn, 2009b) |
ASP1941 = 1:1 complexwith L-proline 8.4 (Washburn, 2009b) |
CanagliflozinTA-7284 2.2 (Nomura et al., 2010) |
|||
7. |
|
8. |
|
9. |
|
0.72 (Song et al., 2011) | 6.5 (Handlon, 2005) | 6 (Washburn, 2009b) | |||
10. |
|
11. |
|
12. |
|
10 (Zhou et al., 2010) | 1.4 (Washburn, 2009b) | 2 (Washburn, 2009b) |
(Entry 7) displayed the best result, however, according to its
From
In the quest of new candidates for SGLT2 inhibition the modification of the sugar part of the molecules is a further possibility. Replacement of the ring oxygen by a sulfur atom provided new potent 1,5-anhydro-1-thio-D-glucitol derivatives (Table 7, Entries 1-3) (Washburn, 2009b). TS-071 (Entry 1) showed excellent urinary glucose excretion in dogs and is currently undergoing phase II clinical trials (Kakinuma et al., 2010). Modification of the glucose moiety by substituting the hydroxyl groups attached to either C-4 or C-6 with fluorine (Entries 4 and 5) also resulted in effective molecules (Washburn, 2009b). Replacement of the hydroxymethyl side chain of the glucose part with a methyl- or methylsulfanyl group (Entries 6 and 7, respectively) provided molecules with good inhibitory effect, from which LX4211 (Entry 7) is a clinical candidate (Washburn, 2009b). Further transformation of the
Entry | Entry | ||
1. |
|
2. |
|
2.9 (Washburn, 2009b) | 1.1 (Washburn, 2009b) | ||
3. |
|
4. |
|
0.9 (Washburn, 2009b) | 2.3 (Washburn, 2009b) | ||
5. |
|
6. |
|
1.5 (Washburn, 2009b) | 0.3 (Lv et al., 2009) |
side chain of the sugar moiety as in the C-5-spirocyclic analogues (Entries 8 and 9) as well as removal of the 4-OH from the glucose ring (Entry 10) furnished compounds exhibiting SGLT2 inhibitory effect in the low nanomolar range (Robinson et al., 2010).
Entry | Entry | ||
1. |
|
2. |
|
TS-071 2.26 (Kakinuma et al., 2010) |
10 (Washburn, 2009b) | ||
3. |
|
4. |
|
12 (Washburn, 2009b) | 5 (Washburn, 2009b) | ||
5. |
|
6. |
|
31 (Washburn, 2009b) | 2.4 (Robinson et al., 2010) | ||
7. |
|
8. |
|
LX4211 (Washburn, 2009b) | 3.4 (Robinson et al., 2010) | ||
9. |
|
10. |
|
3.0 (Robinson et al., 2010) | 21 (Robinson et al., 2010) |
4. Glucose analogue inhibitors of glycogen phosphorylase
The liver accounts for ~90 % of the body's endogenous glucose production. Hepatic glucose is formed via two pathways: glycogenolysis (release of monomeric glucose from the glycogen polymer storage form) and gluconeogenesis (
Glycogen phosphorylases (existing as ‘muscle’, ‘brain’, or ‘liver’ isoforms) are allosterically regulated enzymes consisting of a dimeric arrangement of two identical subunits related to each other by a C2 symmetry. Protein crystallographic studies (Chrysina, 2010; Oikonomakos, 2002) revealed the existence of six binding sites in GP (Fig. 1): the catalytic, the inhibitor, the allosteric, the glycogen storage, and the new allosteric sites, as well as the newly discovered benzimidazole site (Chrysina et al., 2005). Each binding site can be targeted by small molecules, and a large variety of inhibitors were tested as described in recent reviews (Loughlin, 2010; Oikonomakos & Somsák, 2008; Somsák et al., 2008).
Physiological investigations with glycogen phosphorylase inhibitors in the context of T2DM have recently been reviewed (Agius, 2010).
Under physiological conditions glucose (Fig. 2) serves as a regulator of GP since the less active T state of the enzyme is stabilized (Board et al., 1995) by its weak binding to the catalytic centre. This has raised the possibility to search for glucose derivatives with much higher affinity to the active site. A large variety of glucose based compounds were synthesized and tested mainly against the prototype of the GP enzymes, the best available rabbit muscle GP (Chrysina, 2010).
For the inhibitory glucose derivatives (Gimisis, 2010; Praly & Vidal, 2010; Somsák, 2011; Somsák et al., 2003; Somsák et al., 2005) protein crystallography showed primary binding to the catalytic site of the enzyme. Some glucose analogues can also occupy the new allosteric site (Oikonomakos et al., 2002), and the benzimidazole-site was evidenced by a 2-(β-D-glucopyranosyl)-benzimidazole (Chrysina et al., 2005).
The studied
Extensive investigation of
Entry | Compound | R | ||
A | B | C | ||
(Somsák, 2011; Somsák et al., 2008) |
|
|
||
1. |
|
CH3 32 | 81 | 10 |
2. |
|
H 140 | 18 | 5.2 |
3. |
|
- | 4.6 | 0.35 |
4. |
|
- | 21 | - |
(Gimisis, 2010) | -CH3 | -(CH2)2SCH3 |
|
|
5. |
|
510 | 1200 | 350 |
(Alexacou et al., 2010; Deleanu et al., 2008) |
|
|
|
|
6. |
|
33 | 5.7 | 28 |
compounds and b) a large hydrophobic substituent (compare columns B and C) make the best inhibitor (Entry 3C), actually the first glucose analogue in the nanomolar inhibition range. Other structures, e. g. those in Entries 1-2A, are much less efficient. For further detailed analysis of structure-activity relationships of analogous compounds see (Somsák et al., 2008).
Among 1-glucopyranosyl-1,2,3-triazoles (Table 9, Entries 1-3), which can be regarded as non-classical bioisosteres of
Entry | Compound | R | Ki [μM] | |
(Somsák, 2011) | ||||
1. |
|
|
151 | |
2. |
|
16 | ||
3. | -CH2OH | 14 | ||
(Gimisis, 2010; Praly & Vidal, 2010) | ||||
4. |
|
310 | ||
5. |
|
170 | ||
6. |
|
OH | 6.1 | |
7. | F | 3460 | ||
8. |
|
OH | 5.5 | |
9. | F | 3670 | ||
10. |
|
OH | 7.7 | |
11. | F | 4010 | ||
12. |
|
46 | ||
13. |
|
76 |
large aromatic moiety (compare Entries 1 and 2 in Table 9). Interestingly, a polar appendage also led to an inhibitor of similar efficiency (Entry 3).
Entry | Compound | Ki [μM] | ||
(Somsák et al., 2003) | ||||
1. |
|
R = H | 440 | |
2. | R = CH3 | 160 | ||
(Somsák, 2011) | ||||
3. |
|
130 | ||
4. |
|
No inhibition | ||
5. |
|
X = CH2 | 52 % at 100 μM | |
6. | X = NH | 3.5 | ||
7. |
|
No inhibition | ||
8. |
|
X = S | 76 | |
9. | X = NH | 9 | ||
10. |
|
10 % at 625 μM | ||
11. |
|
38 | ||
12. |
|
2.4 |
Glucose derivatives with a substituent attached by a carbon-carbon bond (Table 10, Entries 1-4) showed weak or no inhibition. A comparison of the
The anomeric spiro-hydantoin and -thiohydantoin (Table 11, Entries 1 and 2, respectively) belong to the first efficient compounds of early GP inhibitor design. Changing the sugar part from glucose to xylose (by removal of the CH2OH substituent, Entries 3 and 4) resulted in complete loss of inhibition. Reversal of the spiro-configuration (compare Entries 1 and 5) as well as spiro-annelation of a six-membered ring (Entry 6) gave compounds with significantly weaker binding (Somsák et al., 2003). Extension of the anomeric spirocycles by further ring-condensations as in Entries 7 and 8 produced practically inefficient structures (Gimisis, 2010). Substitution by aromatic groups in the spiro-isoxazolines (Entries 9 and 11) and spiro-oxathiazoles (Entries 10 and 12) gave good inhibitors and the naphthyl derivatives (Entries 11 and 12) are among the best known glucose derived compounds (Somsák, 2011).
Contrary to α-glucosidases, iminosugar type compounds with 5-7 membered rings do not show significant inhibition against GP enzymes: e. g. nojirimicin has no effect, for 1-deoxy-nojirimicin Ki = 55000 μM (for the structures see Table 2) ( Compain et al., 2007 ). There are a few exceptions to this such as DAB and isofagomine derivatives (Fig. 3) (Praly & Vidal, 2010; Somsák et al., 2008; Somsák et al., 2003). A comprehensive tabulation of glycogen phosphorylase inhibition studies with iminosugars can be found in (Compain et al., 2007).
Entry | Compound | X | Ki [μM] | |
(Somsák et al., 2003) | ||||
1. |
|
O | 3.1 | |
2. | S | 5.1 | ||
3. |
|
O | No inhibition | |
4. | S | No inhibition | ||
5. |
|
320 | ||
6. |
|
59 | ||
(Gimisis, 2010) | ||||
7. |
|
~2100 | ||
8. |
|
~1700 | ||
(Somsák, 2011) | ||||
9. |
|
CH2 | 19.6 | |
10. | S | 26 | ||
11. |
|
CH2 | 0.63 | |
12. | S | 0.16 |
Miscellaneous sugar derivatives including further
While no physiological investigations with glucose analogue inhibitors of GP can be found in the literature, very recently it has been demonstrated that glucopyranosylidene-spiro-thiohydantoin (Table 11, Entry 2) is effective in lowering blood glucose levels and restoring hepatic glycogen content in streptozotocin-induced diabetic rats (Docsa et al., 2011).
5. Conclusion
This survey provided an overview of carbohydrate derivatives and sugar like compounds (glycomimetics) which are employed in current therapies or investigated as potential future medications for type 2 diabetes mellitus. Although these applications and explorations do not exceed the symptomatic level of treatments characteristic of present curing, they promise the possibility of broadening the arsenal of the physician. Together with several other carbohydrate-based therapeutics these drugs and studied molecules pave the way for a more extensive use of saccharides in medicine.
6. Abbreviations
DPP-4 dipeptidyl-peptidase-4 6PF-2-K 6-phosphofructo-2-kinase F-1,6-P2ase fructose-1,6-bisphosphatase PLGP pig liver glycogen phosphorylase F-2,6-P2 fructose-2,6-bisphosphate PPAR peroxisome proliferator-activated receptor G-6-Pase glucose-6-phosphatase PTP-1B protein tyrosin phosphatase-1B GCK glucokinase RLGP rat liver glycogen phosphorylase GLP-1 glucagon-like peptide-1 RMGP rabbit muscle glycogen phosphorylase GLUT glucose transporter SAR structure-activity relationship GP glycogen phosphorylase SGLT sodium dependent glucose transporter GPI glycogen phosphorylase inhibitor T2DM type 2 diabetes mellitus GSK3 glycogen synthase kinase-3
Acknowledgments
This work was supported by the Hungarian Scientific Research Fund (OTKA CK 77712) and by the TÁMOP 4.2.1/B-09/1/KONV-2010-0007 project co-financed by the European Union and the European Social Fund.
References
- 1.
Agius L. 2010 Physiological control of liver glycogen metabolism: Lessons from novel glycogen phosphorylase inhibitors.10 1175 1187 . - 2.
Alberti G. Zimmet P. Shaw J. Bloomgarden Z. Kaufman F. Silink M. 2004 Type 2 diabetes in the young: The evolving epidemic- The International Diabetes Federation Consensus Workshop.27 1798 1811 . - 3.
Alexacou K. M. Tenchiu A. C. Chrysina E. D. Charavgi M. D. Kostas I. D. Zographos S. E. Oikonomakos N. G. Leonidas D. D. 2010 The binding of β-D-glucopyranosyl-thiosemicarbazone derivatives to glycogen phosphorylase: A new class of inhibitors.18 7911 7922 . - 4.
Andersen B. Rassov A. Westergaard N. Lundgren K. 1999 Inhibition of glycogenolysis in primary rat hepatocytes by 1,4-dideoxy-1,4-imino-arabinitol.342 545 550 . - 5.
Asano N. 2009 Sugar-mimicking glycosidase inhibitors: bioactivity and application.66 1479 1492 . - 6.
Bailey C. J. 2011 Renal glucose reabsorption inhibitors to treat diabetes.32 63 71 . - 7.
Barroso I. 2005 Genetics of type 2 diabetes.22 517 535 . - 8.
Bloomgarden Z. T. 2004 Type 2 diabetes in the young- The evolving epidemic.27 998 1010 . - 9.
Board M. Hadwen M. Johnson L. N. 1995 Effects of novel analogs of D-glucose on glycogen-phosphorylase activities in crude extracts of liver and skeletal-muscle.228 753 761 . - 10.
Boldys A. Okopien B. 2009 Inhibitors of type 2 sodium glucose co-transporters- a new strategy for diabetes treatment.61 778 784 . - 11.
Bonnefond A. Froguel P. Vaxillaire M. 2010 The emerging genetics of type 2 diabetes.16 407 416 . - 12.
Brownlee M. 2001 Biochemistry and molecular cell biology of diabetic complications.414 813 820 . - 13.
Cheng A. Y. Y. Fantus I. G. 2005 Oral antihyperglycemic therapy for type 2 diabetes mellitus.172 213 226 . - 14.
Chrysina E. D. 2010 The prototype of glycogen phosphorylase.10 1093 1101 . - 15.
Chrysina E. D. Kosmopolou M. N. Tiraidis C. Kardarakis R. Bischler N. Leonidas D. D. Hadady Z. Somsák L. Docsa T. Gergely P. Oikonomakos N. G. 2005 Kinetic and crystallographic studies on 2-(β-D-glucopyranosyl)-5-methyl-1,3,4-oxadiazole,-benzothiazole, and-benzimidazole, inhibitors of muscle glycogen phosphorylase b. Evidence for a new binding site.14 873 888 . - 16.
Compain P. Desvergnes V. Liautard V. Pillard C. Toumieux S. 2007 Tables of iminosugars, their biological activities and their potential as therapeutic agents. In: . Compain, P. & Martin, O. R. (Ed(s).). Chichester, John Wiley & Sons Ltd.327 455 . - 17.
Compain P. Martin O. R. 2007 Iminosugars: From synthesis to therapeutic applications. Chichester, John Wiley & Sons Ltd. - 18.
de Melo E. B. Gomes A. D. Carvalho I. 2006 α- and β-Glucosidase inhibitors: chemical structure and biological activity.62 10277 10302 . - 19.
Deleanu A. C. Kostas I. D. Liratzis I. Alexacou K. M. Leonidas D. D. Zographos S. E. Oikonomakos N. G. 2008 β-D-Glucopyranosyl-modified thiosemicarbazones as inhibitors of glycogen phosphorylase. Dobogókő, Hungary, September 8-11, 2008. Book of Abstracts80 - 20.
Diamond J. 2003 The double puzzle of diabetes.423 599 602 . - 21.
Docsa T. Czifrák K. Hüse C. Somsák L. Gergely P. 2011 The effect of glucopyranosylidene-spiro-thiohydantoin on the glycogen metabolism in liver tissues of streptozotocin-induced and obese diabetic rats.4 477 481 . - 22.
Ehrenkranz J. R. L. Lewis N. G. Kahn C. R. Roth J. 2005 Phlorizin: a review.21 31 38 . - 23.
Ehtisham S. Barrett T. G. 2004 The emergence of type 2 diabetes in childhood.41 10 16 . - 24.
El Ashry E. S. H. Rashed N. Shobier A. H. S. 2000a Glycosidase inhibitors and their chemotherapeutic value, part 1.55 251 262 . - 25.
El Ashry E. S. H. Rashed N. Shobier A. H. S. 2000b Glycosidase inhibitors and their chemotherapeutic value, part 2.55 331 348 . - 26.
El Ashry E. S. H. Rashed N. Shobier A. H. S. 2000c Glycosidase inhibitors and their chemotherapeutic value, part 3.55 403 415 . - 27.
Fujimori Y. Katsuno K. Nakashima I. Ishikawa-Takemura Y. Fujikura H. Isaji M. 2008 Remogliflozin etabonate, in a novel category of selective low-affinity sodium glucose cotransporter (SGLT2) inhibitors, exhibits antidiabetic efficacy in rodent models.327 268 276 . - 28.
Geschwind J. F. Georgiades C. S. Ko Y. H. Pedersen P. L. 2004 Recently elucidated energy catabolism pathways provide opportunities for novel treatments in hepatocellular carcinoma. Expert Review of Anticancer Therapy,4 449 457 . - 29.
Gimisis T. 2010 Synthesis of N-glucopyranosidic derivatives as potential inhibitors that bind at the catalytic site of glycogen phosphorylase.10 1127 1138 . - 30.
Green A. Hirsch N. C. Pramming S. K. 2003 The changing world demography of type 2 diabetes.19 3 7 . - 31.
Handlon A. L. 2005 Sodium glucose co-transporter 2 (SGLT2) inhibitors as potential antidiabetic agents.15 1531 1540 . - 32.
Hanhineva K. Torronen R. Bondia-Pons I. Pekkinen J. Kolehmainen M. Mykkanan H. Poutanen K. 2010 Impact of dietary polyphenols on carbohydrate metabolism.11 1365 1402 . - 33.
Hengesh E. J. 1995 Drugs affecting sugar metabolism. In: . Foye, W. O., Lemke, T. L. & Williams, D. A. (Ed(s).). Baltimore, Williams & Wilkins.581 600 . - 34.
Home G. Wilson F. X. Tinsley J. Williams D. H. Storer R. 2011 Iminosugars past, present and future: medicines for tomorrow.16 107 118 . - 35.
Idris I. Donnelly R. 2009 Sodium-glucose co-transporter-2 inhibitors: an emerging new class of oral antidiabetic drug.11 79 88 . - 36.
Isaji M. 2007 Sodium-glucose cotransporter inhibitors for diabetes.8 285 292 . - 37.
Israili Z. H. 2011 Advances in the treatment of type 2 diabetes mellitus. American Journal of Therapeutics,18 117 152 . - 38.
Kakinuma H. Oi T. Hashimoto-Tsuchiya Y. Arai M. Kawakita Y. Fukasawa Y. Iida I. Hagima N. Takeuchi H. Chino Y. Asami J. Okumura-Kitajima L. Io F. Yamamoto D. Miyata N. Takahashi T. Uchida S. Yamamoto K. 2010 (1S)-1,5-Anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-D-glucitol (TS-071) is a potent, selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for type 2 diabetes treatment.53 3247 3261 . - 39.
Katsuno K. Fujimori Y. Takemura Y. Hiratochi M. Itoh F. Komatsu Y. Fujikura H. Isaji M. 2007 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.320 323 330 . - 40.
Kim M. J. Lee J. Kang S. Y. Lee S. H. Son E. J. Jung M. E. Lee S. H. Song K. S. Lee M. Han H. K. Kim J. Lee J. 2010 Novel C-aryl glucoside SGLT2 inhibitors as potential antidiabetic agents: pyridazinylmethylphenyl glucoside congeners.20 3420 3425 . - 41.
Krentz A. J. Bailey C. J. 2005 Oral antidiabetic agents- current role in type 2 diabetes mellitus.65 385 411 . - 42.
Kurukulasuriya R. Link J. T. Madar D. J. Pei Z. Richards S. J. Rohde J. J. Souers A. J. Szczepankiewicz B. G. 2003 Potential drug targets and progress towards pharmacologic inhibition of hepatic glucose production.10 123 153 . - 43.
Lee J. Kim J. Y. Choi J. Lee S. H. Kim J. Lee J. 2010a Pyrimidinylmethylphenyl glucoside as novel C-aryl glucoside SGLT2 inhibitors.20 7046 7049 . - 44.
Lee J. Lee S. H. Seo H. J. Son E. J. Lee S. H. Jung M. E. Lee M. Han H. K. Kim J. Kang J. Lee J. 2010b Novel C-aryl glucoside SGLT2 inhibitors as potential antidiabetic agents: 1,3,4-thiadiazolylmethylphenyl glucoside congeners.18 2178 2194 . - 45.
Lillelund V. H. Jensen H. H. Liang X. Bols M. 2002 Recent developments of transition-state analogue glycosidase inhibitors of non-natural product origin.102 515 553 . - 46.
Loughlin W. A. 2010 Recent advances in the allosteric inhibition of glycogen phosphorylase.10 1139 1155 . - 47.
Lowell B. B. Shulman G. I. 2005 Mitochondrial dysfunction and type 2 diabetes.307 384 387 . - 48.
Lv B. H. Xu B. H. Feng Y. Peng K. Xu G. Du J. Y. Zhang L. L. Zhang W. B. Zhang T. Zhu L. C. Ding H. F. Sheng Z. L. Welihinda A. Seed B. Chen Y. W. 2009 Exploration of O-spiroketal C-arylglucosides as novel and selective renal sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors.19 6877 6881 . - 49.
Meng W. Ellsworth B. A. Nirschl A. A. Mc Cann P. J. Patel M. Girotra R. N. Wu G. Sher P. M. Morrison E. P. Biller S. A. Zahler R. Deshpande P. P. Pullockaran A. Hagan D. L. Morgan N. Taylor J. R. Obermeier M. T. Humphreys W. G. Khanna A. Discenza L. Robertson J. G. Wang A. Hang S. Wetterau J. R. Janovitz E. B. Flint O. P. Whaley J. M. Washburn W. N. 2008 Discovery of dapagliflozin: A potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes.51 1145 1149 . - 50.
Mizuno C. S. Chittiboyina A. G. Kurtz T. W. Pershadsingh H. A. Avery M. A. 2008 Type 2 diabetes and oral antihyperglycemic drugs.15 61 74 . - 51.
Mohan S. Pinto B. M. 2007 Zwitterionic glycosidase inhibitors: salacinol and related analogues.342 1551 1580 . - 52.
Moller D. E. 2001 New drug targets for type 2 diabetes and the metabolic syndrome. Nature,414 821 827 . - 53.
Morral N. 2003 Novel targets and therapeutic strategies for type 2 diabetes.14 169 175 . - 54.
Muraoka O. Morikawa T. Miyake S. Akaki J. Ninomiya K. Pongpiriyadacha Y. Yoshikawa M. 2011 Quantitative analysis of neosalacinol and neokotalanol, another two potent alpha-glucosidase inhibitors from Salacia species, by LC-MS with ion pair chromatography.65 142 148 . - 55.
Nomura S. 2010 Renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for new anti-diabetic agent.10 411 418 . - 56.
Nomura S. Sakamaki S. Hongu M. Kawanishi E. Koga Y. Sakamoto T. Yamamoto Y. Ueta K. Kimata H. Nakayama K. Tsuda-Tsukimoto M. 2010 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.53 6355 6360 . - 57.
Nourparvar A. Bulotta A. Di Mario U. Perfetti R. 2004 Novel strategies for the pharmacological management of type 2 diabetes.25 86 91 . - 58.
Oikonomakos N. G. 2002 Glycogen phosphorylase as a molecular target for type 2 diabetes therapy.3 561 586 . - 59.
Oikonomakos N. G. Kosmopolou M. Zographos S. E. Leonidas D. D. Somsák L. Nagy V. Praly J. P. Docsa T. Tóth B. Gergely P. 2002 Binding of N-acetyl-N’-β-D-glucopyranosyl urea and N-benzoyl-N’-β-D-glucopyranosyl urea to glycogen phosphorylase b: Kinetic and crystallographic studies.269 1684 1696 . - 60.
Oikonomakos N. G. Somsák L. 2008 Recent advances in glycogen phosphorylase inhibitor design.9 379 395 . - 61.
Padwal R. Majumdar S. R. Johnson J. A. Varney J. Mc Alister F. A. 2005 A systematic delay or pre review of drug therapy to delay or prevent type 2 diabetes.28 736 744 . - 62.
Panunti B. Jawa A. A. Fonseca V. A. 2004 Mechanisms and therapeutic targets in type 2 diabetes mellitus.1 151 157 . - 63.
Praly J. P. Vidal S. 2010 Inhibition of glycogen phosphorylase in the context of type 2 diabetes, with focus on recent inhibitors bound at the active site.10 1102 1126 . - 64.
Rendell M. 2004 The role of sulphonylureas in the management of type 2 diabetes mellitus.64 1339 1358 . - 65.
Robinson R. P. Mascitti V. Boustany-Kari C. M. Carr C. L. Foley P. M. Kimoto E. Leininger M. T. Lowe A. Klenotic M. K. Mac Donald. J. I. Maguire R. J. Masterson V. M. Maurer T. S. Miao Z. Patel J. D. Preville C. Reese M. R. She L. Steppan C. M. Thuma B. A. Zhu T. 2010 C-Aryl glycoside inhibitors of SGLT2: exploration of sugar modifications including C-5 spirocyclization.20 1569 1572 . - 66.
Ross S. A. Gulve E. A. Wang M. H. 2004 Chemistry and biochemistry of type 2 diabetes.104 1255 1282 . - 67.
Santer R. Calado J. 2010 Familial renal glucosuria and SGLT2: From a Mendelian trait to a therapeutic target.5 133 141 . - 68.
Scheen A. J. 2003 Is there a role for α-glucosidase inhibitors in the prevention of type 2 diabetes mellitus?63 933 951 . - 69.
Schnier J. B. Nishi K. Monks A. Gorin F. A. Bradbury E. M. 2003 Inhibition of glycogen phosphorylase (GP) by CP-91,149 induces growth inhibition correlating with brain GP expression.309 126 134 . - 70.
Sladek, R., Rocheleau, G., Rung, J., Dina, C., Lishuang, S., Serre, D., Boutin, P., Vincent, D., Belisle, A., Hadjadj, S., Balkau, B., Heude, B., Charpentier, G., Hudson, T. J., Montpetit, A., Pshezhetsky, A. V., Prentki, M., Posner, B. I., Balding, D. J., Meyre, D., Sladek, R., Rocheleau, G., Rung, J., Dina, C., Shen, L., Serre, D., Boutin, P., Vincent, D., Belisle, A., Hadjadj, S., Balkau, B., Heude, B., Charpentier, G., Hudson, T. J., Montpetit, A., Pshezhetsky, A. V., Prentki, M., Posner, B. I., Balding, D. J., Meyre, D., Polychronakos, C., Sladek, R., Rocheleau, G., Rung, J., Dina, C., Shen, L., Serre, D., Boutin, P., Vincent, D., Belisle, A., Hadjadj, S., Balkau, B., Heude, B., Charpentier, G., Hudson, T. J., Montpetit, A., Pshezhetsky, A. V., Prentki, M., Posner, B. I., Balding, D. J., Meyre, D., Polychronakos, C., Froguel, P., Sladek, R., Rocheleau, G., Rung, J., Dina, C., Shen, L., Serre, D., Boutin, P., Vincent, D., Belisle, A., Hadjadj, S., Balkau, B., Heude, B., Charpentier, G., Hudson, T. J., Montpetit, A., Pshezhetsky, A. V., Prentki, M., Posner, B. I., Balding, D. J., Meyre, D., Polychronakos, C. & Froguel, P. (2007) . A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature, Vol. 445, pp. 881-885. - 71.
Somsák L. 2011 Glucose derived inhibitors of glycogen phosphorylase.14 211 223 . - 72.
Somsák L. Czifrák K. Tóth M. Bokor É. Chrysina E. D. Alexacou K. M. Hayes J. M. Tiraidis C. Lazoura E. Leonidas D. D. Zographos S. E. Oikonomakos N. G. 2008 New inhibitors of glycogen phosphorylase as potential antidiabetic agents.15 2933 2983 . - 73.
Somsák L. Nagy V. Hadady Z. Docsa T. Gergely P. 2003 Glucose analog inhibitors of glycogen phosphorylases as potential antidiabetic agents: recent developments.9 1177 1189 . - 74.
Somsák L. Nagy V. Hadady Z. Felföldi N. Docsa T. Gergely P. 2005 Recent developments in the synthesis and evaluation of glucose analog inhibitors of glycogen phosphorylases as potential antidiabetic agents. In: . Reitz, A. B., Kordik, C. P., Choudhary, M. I. & Rahman, A. u. (Ed(s).). Bentham.253 272 . - 75.
Song K. S. Lee S. H. Kim M. J. Seo H. J. Lee J. Lee S. H. Jung M. E. Son E. J. Lee M. Kim J. Lee J. 2011 Synthesis and SAR of thiazolylmethylphenyl glucoside as novel C-aryl glucoside SGLT2 inhibitors.2 182 187 . - 76.
Stumvoll M. Goldstein B. J. van Haeften T. W. 2005 Type 2 diabetes: principles of pathogenesis and therapy.365 1333 1346 . - 77.
Sun H. Xu L. 2010 Pharmacological manipulation of brain glycogenolysis as a therapeutic approach to cerebral ischemia.10 1188 1193 . - 78.
Toye A. Gauguier D. 2003 Genetics and functional genomics of type 2 diabetes mellitus.4 241 - 79.
Tracey W. Treadway J. Magee W. Mc Pherson R. Levy C. Wilder D. Li Y. Yue C. Zavadoski W. Gibbs E. Smith A. Flynn D. Knight D. 2003 A novel glycogen phosphorylase inhibitor, CP-368296, reduces myocardial ischemic injury.52 A135 A135 . - 80.
Tracey W. R. Treadway J. L. Magee W. P. Sutt J. C. Mc Pherson R. K. Levy C. B. Wilder D. E. Yu L. J. Chen Y. Shanker R. M. Mutchler A. K. Smith A. H. Flynn D. M. Knight D. R. 2004 Cardioprotective effects of ingliforib, a novel glycogen phosphorylase inhibitor.286 H1177 H1184 . - 81.
Treadway J. L. Mendys P. Hoover D. J. 2001 Glycogen phosphorylase inhibitors for treatment of type 2 diabetes mellitus.10 439 454 . - 82.
Tundis R. Loizzo M. R. Menichini F. 2010 Natural products as α-amylase and α-glycosidase inhibitors and their hypoglycaemic potential in the treatment of diabetes: An update.10 315 331 . - 83.
Uwaifo G. I. Ratner R. E. 2005 Novel pharmacologic agents for type 2 diabetes.34 155 197 . - 84.
Vaidya H. B. Goyal R. K. 2010 Exploring newer target sodium glucose transporter 2 for the treatment of diabetes mellitus.10 905 913 . - 85.
Wagman A. S. Johnson K. W. Bussiere D. E. 2004 Discovery and development of GSK3 inhibitors for the treatment of type 2 diabetes.10 1105 1137 . - 86.
Wagman A. S. Nuss J. M. 2001 Current therapies and emerging targets for the treatment of diabetes.7 417 450 . - 87.
Washburn W. N. 2009a Development of the renal glucose reabsorption inhibitors: A new mechanism for the pharmacotherapy of diabetes mellitus type 2 . ,52 1785 1794 . - 88.
Washburn W. N. 2009b Evolution of sodium glucose co-transporter 2 inhibitors as anti-diabetic agents.19 1485 1499 . - 89.
Wright E. M. 2001 Renal Na+-glucose cotransporters.280 F10 F18 . - 90.
Xie W. Tanabe G. Akaki J. Morikawa T. Ninomiya K. Minematsu T. Yoshikawa M. Wu X. Muraoka O. 2011 Isolation, structure identification and SAR studies on thiosugar sulfonium salts, neosalaprinol and neoponkoranol, as potent [alpha]-glucosidase inhibitors.19 2015 2022 . - 91.
Xu B. H. Feng Y. Lv B. H. Xu G. Zhang L. L. Du J. Y. Peng K. Xub M. Dong J. J. Zhang W. B. Zhang T. Zhu L. C. Ding H. F. Sheng Z. L. Welihinda A. Seed B. Chen Y. W. 2010 ortho-Substituted C-aryl glucosides as highly potent and selective renal sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors.18 4422 4432 . - 92.
Zechel D. L. Withers S. G. 2000 Glycosidase mechanisms: Anatomy of a finely tuned catalyst.33 11 18 . - 93.
Zhou H. Q. Danger D. P. Dock S. T. Hawley L. Roller S. G. Smith C. D. Handlon A. L. 2010 Synthesis and SAR of benzisothiazole- and indolizine-β-D-glucopyranoside inhibitors of SGLT2.1 19 23 .