dapagliflozin and Diabetes-Mellitus--Type-2

Gliflozins constitute an important class of compounds useful as sodium glucose co-transporter (SGLT2) inhibitors to treat type-II diabetes. They act by blocking sodium-glucose transport protein 2 which is responsible for re-absorption of glucose in the proximal convoluted tubule (PCT) of kidney and thus its inhibition reduces blood glucose level. There are a number of gliflozins which have been approved by drug regulatory bodies like FDA, EMA and PMDA whereas some others are in pipeline in their late developmental phases. The present review article offers a detailed account of synthetic strategies employed for the synthesis, alternate synthetic routes along with Structure Activity Relationship (SAR) studies of well-established as well as newly developed SGLT2 inhibitors.

Topics: Animals; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Glucosides; Humans; Hypoglycemic Agents; Molecular Structure; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Structure-Activity Relationship

Topics: Animals; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Evaluation, Preclinical; Glucose; Glucosides; Humans; Hypoglycemic Agents; Kidney; Sodium-Glucose Transporter 2 Inhibitors

Sodium-dependent glucose co-transporter 2 (SGLT2) has emerged as a promising drug target for the treatment of type 2 diabetes, and recently, several SGLT2 inhibitors have been approved for clinical use. A series of molecules with a C-aryl glucoside scaffold was designed and synthesized for biological evaluation. Among the molecules tested, a dihydrobenzofuran-containing analog, 14g (GCC5694A), exhibited excellentin vitro activity against SGLT2 (IC

Topics: Administration, Oral; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Discovery; Humans; Molecular Structure; Rats; Rats, Sprague-Dawley; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Structure-Activity Relationship

Topics: Animals; Benzhydryl Compounds; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Design; Glucosides; Mice; Mice, Inbred C57BL; Molecular Structure; Rats; Rats, Sprague-Dawley; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Spiro Compounds; Structure-Activity Relationship

The cardiovascular complications were highly prevalent in type 2 diabetes mellitus (T2DM), even at the early stage of T2DM or the state of intensive glycemic control. Therefore, there is an urgent need for the intervention of cardiovascular complications in T2DM. Herein, the new hybrids of NO donor and SGLT2 inhibitor were design to achieve dual effects of anti-hyperglycemic and anti-thrombosis. As expected, the preferred hybrid 2 exhibited moderate SGLT2 inhibitory effects and anti-platelet aggregation activities, and its anti-platelet effect mediated by NO was also confirmed in the presence of NO scavenger. Moreover, compound 2 revealed significantly hypoglycemic effects and excretion of urinary glucose during an oral glucose tolerance test in mice. Potent and multifunctional hybrid, such as compound 2, is expected as a potential candidate for the intervention of cardiovascular complications in T2DM.

Topics: Adenosine Diphosphate; Animals; Benzhydryl Compounds; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Design; Glucose Tolerance Test; Glucosides; HEK293 Cells; Humans; Hypoglycemic Agents; Male; Mice; Mice, Inbred ICR; Molecular Structure; Nitric Oxide; Platelet Aggregation; Rabbits; Structure-Activity Relationship; Venous Thrombosis

Inhibiting glucose reabsorption by sodium glucose co-transporter proteins (SGLTs) in the kidneys is a relatively new strategy for treating type 2 diabetes. Selective inhibition of SGLT2 over SGLT1 is critical for minimizing adverse side effects associated with SGLT1 inhibition. A library of C-glucosyl dihydrochalcones and their dihydrochalcone and chalcone precursors was synthesized and tested as SGLT1/SGLT2 inhibitors using a cell-based fluorescence assay of glucose uptake. The most potent inhibitors of SGLT2 (IC

Topics: Chalcones; Diabetes Mellitus, Type 2; Glucosides; HEK293 Cells; Humans; Membranes, Artificial; Molecular Docking Simulation; Phosphatidylcholines; Sodium-Glucose Transporter 1; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

A new class of potent and highly selective SGLT2 inhibitors is disclosed. Compound 31 (HSK0935) demonstrated excellent hSGLT2 inhibition of 1.3 nM and a high hSGLT1/hSGLT2 selectivity of 843-fold. It showed robust urinary glucose excretion in Sprague-Dawley (SD) rats and affected more urinary glucose excretion in Rhesus monkeys. Finally, an efficient synthetic route has been developed featuring a ring-closing cascade reaction to incorporate a double ketal 1-methoxy-6,8-dioxabicyclo[3.2.1]octane ring system.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; CHO Cells; Cricetulus; Diabetes Mellitus, Type 2; Glucose; Glycosuria; Humans; Hypoglycemic Agents; Kidney; Macaca mulatta; Male; Mice, Inbred ICR; Rats, Sprague-Dawley; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

A series of novel tetrahydroisoquinoline-C-aryl glucosides has been synthesized and evaluated for the inhibition of human SGLT2. Compared with dapagliflozin, compound 13h exhibited equivalent in vitro inhibitory activity against SGLT2, which might become a promising candidate for the treatment of type 2 diabetes.

Topics: Animals; CHO Cells; Cricetulus; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Glucosides; Humans; Hypoglycemic Agents; Molecular Structure; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Structure-Activity Relationship; Tetrahydroisoquinolines

SGLT2 inhibitors deuterated at sites susceptible to oxidative metabolism were found to have a slightly longer tmax and half-life (t1/2), dose-dependent increase in urinary glucose excretion (UGE) in rats, and slightly superior effects on UGE in dogs while retaining similar in vitro inhibitory activities against hSGLT2. In particular, deuterated compound 41 has the potential to be a robust long-acting antidiabetic agent.

Topics: Animals; Diabetes Mellitus, Type 2; Glycosides; Magnetic Resonance Spectroscopy; Rats; Rats, Sprague-Dawley; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Spectrometry, Mass, Electrospray Ionization

C-Aryl 5a-carba-β-d-glucopyranose derivatives were synthesized and evaluated for inhibition activity against hSGLT1 and hSGLT2. Modifications to the substituents on the two benzene rings resulted in enhanced hSGLT2 inhibition activity and extremely high hSGLT2 selectivity versus SGLT1. Using the created superimposed model, the reason for the high hSGLT2 selectivity was speculated to be that additional substituents occupied a new space, in a different way than known inhibitors. Among the tested compounds, the ethoxy compound 5h with high hSGLT2 selectivity exhibited more potent and longer hypoglycemic action in db/db mice than our O-carbasugar compound (1) and sergliflozin (2), which could be explained by its improved PK profiles relative to those of the two compounds. These results indicated that 5h might be a promising drug candidate for the treatment of type 2 diabetes.

Topics: Administration, Oral; Animals; Area Under Curve; Blood Glucose; Cyclohexanols; Diabetes Mellitus, Type 2; Glucose; Hypoglycemic Agents; Mice; Mice, Obese; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Structure-Activity Relationship

Inhibition of sodium glucose cotransporter 2 (SGLT2) has been proposed as a novel therapeutic approach to treat type 2 diabetes. In our efforts to discover novel inhibitors of SGLT2, we first generated a 3D pharmacophore model based on the superposition of known inhibitors. A search of the Cambridge Structural Database using a series of pharmacophore queries led to the discovery of an O-spiroketal C-arylglucoside scaffold. Subsequent chemical examination combined with computational modeling resulted in the identification of the clinical candidate 16d (CSG452, tofogliflozin), which is currently under phase III clinical trials.

Topics: Animals; Benzhydryl Compounds; Diabetes Mellitus, Type 2; Glucosides; Humans; Macaca fascicularis; Magnetic Resonance Spectroscopy; Mice; Mice, Inbred ICR; Models, Molecular; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Spectrometry, Mass, Electrospray Ionization

A novel series of N-linked β-D-xylosides were synthesized and evaluated for inhibitory activity against sodium-dependent glucose cotransporter 2 (SGLT2) in a cell-based assay. Of these, the 4-chloro-3-(4-cyclopropylbenzyl)-1-(β-D-xylopyranosyl)-1H-indole 19m was found to be the most potent inhibitor, with an EC(50) value similar to that of the natural SGLT2 inhibitor phlorizin. Further studies in Sprague-Dawley (SD) rats indicated that 19m significantly increased urine glucose excretion in a dose-dependent manner with oral administration. The antihyperglycemic effect of 19m was also observed in streptozotocin (STZ) induced diabetic SD rats. These results described here are a good starting point for further investigations into N-glycoside SGLT2 inhibitors.

Topics: Animals; CHO Cells; Cricetinae; Cricetulus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Glucose; Glucosides; Humans; Hyperglycemia; Hypoglycemic Agents; Indoles; Male; Mice; Mice, Inbred ICR; Rats; Rats, Sprague-Dawley; Sodium-Glucose Transporter 2 Inhibitors; Structure-Activity Relationship; Xylose

A series of C-aryl glucosides with various substituents at the 4'-position of the distal aryl ring have been synthesized and evaluated for inhibition of hSGLT1 and hSGLT2. Introduction of alkyl or alkoxy substituents at the 4'-position was found to improve SGLT2 potency, whereas introduction of a hydrophilic group at this position was deleterious. Compounds with alkoxy-, cycloalkoxy- or cycloalkenyloxy-ethoxy scaffolds exhibited good inhibitory activity and high selectivity toward SGLT2. Selected compounds were investigated for in vivo efficacy.

Topics: Diabetes Mellitus, Type 2; Glucosides; Humans; Hypoglycemic Agents; Sodium-Glucose Transporter 1; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Structure-Activity Relationship

Derivatives of a novel scaffold, C-phenyl 1-thio-D-glucitol, were prepared and evaluated for sodium-dependent glucose cotransporter (SGLT) 2 and SGLT1 inhibition activities. Optimization of substituents on the aromatic rings afforded five compounds with potent and selective SGLT2 inhibition activities. The compounds were evaluated for in vitro human metabolic stability, human serum protein binding (SPB), and Caco-2 permeability. Of them, (1S)-1,5-anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-D-glucitol (3p) exhibited potent SGLT2 inhibition activity (IC(50) = 2.26 nM), with 1650-fold selectivity over SGLT1. Compound 3p showed good metabolic stability toward cryo-preserved human hepatic clearance, lower SPB, and moderate Caco-2 permeability. Since 3p should have acceptable human pharmacokinetics (PK) properties, it could be a clinical candidate for treating type 2 diabetes. We observed that compound 3p exhibits a blood glucose lowering effect, excellent urinary glucose excretion properties, and promising PK profiles in animals. Phase II clinical trials of 3p (TS-071) are currently ongoing.

Topics: Animals; Biological Availability; Blood Proteins; Caco-2 Cells; Cell Membrane Permeability; CHO Cells; Cricetinae; Cricetulus; Diabetes Mellitus, Type 2; Dogs; Hepatocytes; Humans; Hypoglycemic Agents; In Vitro Techniques; Microsomes, Liver; Protein Binding; Rats; Rats, Zucker; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Sorbitol; Structure-Activity Relationship; Tissue Distribution

The prevalence of diabetes throughout the world continues to increase and has become a major health issue. Recently there have been several reports of inhibitors directed toward the sodium-dependent glucose cotransporter 2 (SGLT2) as a method of maintaining glucose homeostasis in diabetic patients. Herein we report the discovery of the novel O-xyloside 7c that inhibits SGLT2 in vitro and urinary glucose reabsorption in vivo.

Topics: Animals; Diabetes Mellitus, Type 2; Drug Discovery; Glucose; Humans; Mice; Sodium-Glucose Transporter 2 Inhibitors; Substrate Specificity; Xylose

The C-aryl glucoside 6 (dapagliflozin) was identified as a potent and selective hSGLT2 inhibitor which reduced blood glucose levels in a dose-dependent manner by as much as 55% in hyperglycemic streptozotocin (STZ) rats. These findings, combined with a favorable ADME profile, have prompted clinical evaluation of dapagliflozin for the treatment of type 2 diabetes.

Topics: Administration, Oral; Animals; Benzhydryl Compounds; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Glucosides; Humans; Hypoglycemic Agents; Kidney; Rats; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Stereoisomerism