sergliflozin-etabonate and Diabetes-Mellitus--Type-2

Sodium-glucose cotransporter 2 (SGLT-2) inhibitors (gliflozins) represent the most recently approved class of oral antidiabetic drugs. SGLT-2 overexpression in diabetic patients contributes significantly to hyperglycemia and related complications. Therefore, SGLT-2 became a highly interesting therapeutic target, culminating in the approval for clinical use of dapagliflozin and analogues in the past decade. Gliflozins improve glycemic control through a novel insulin-independent mechanism of action and, moreover, exhibit significant cardiorenal protective effects in both diabetic and nondiabetic subjects. Therefore, gliflozins have received increasing attention, prompting extensive structure-activity relationship studies and optimization approaches. The discovery that intestinal SGLT-1 inhibition can provide a novel opportunity to control hyperglycemia, through a multifactorial mechanism, recently encouraged the design of low adsorbable inhibitors selectively directed to the intestinal SGLT-1 subtype as well as of dual SGLT-1/SGLT-2 inhibitors, representing a compelling strategy to identify new antidiabetic drug candidates.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Humans; Hyperglycemia; Hypoglycemic Agents; Sodium; Sodium-Glucose Transporter 2 Inhibitors

1. Several sodium-glucose cotransporter-2 (SGLT-2) inhibitors are in clinical use for the management of type 2 diabetes. The objectives of the current review were: (a) to provide a comparative pharmacokinetics including absorption, distribution, metabolism and excretory (ADME) profiles of three SGLT-2 inhibitors namely: sergliflozin, remogliflozin and ertugliflozin; (b) to provide some perspectives on possible developmental issues. 2. Based on the half-life (t

Topics: Blood Glucose; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Glucosides; Half-Life; Humans; Hypoglycemic Agents; Pyrazoles; Sodium-Glucose Transporter 2

Current options for glycemic control are less than optimal in terms of efficacy and to reduce complications in the diabetic population. Selective inhibition of SGLT2 in the proximal tubule increases urinary glucose excretion thereby reducing plasma glucose levels, which may present a novel therapeutic approach.. SGLT2 inhibitors enhance glucose excretion and improve glycemic control in patients with type 2 diabetes in the absence of clinically relevant hypoglycemia or sustained changes in volume status or glomerular filtration rate. This is associated with lowering of body weight and may reduce systolic blood pressure. The increased glucosuria appears to increase the risk of genital infections but may not increase the risk of urinary tract infections.. The ability of SGLT2 inhibitors to reduce plasma glucose without inducing increased insulin secretion, clinically relevant hypoglycemia, or weight gain constitutes a major advance. The ability to increase glucose excretion provides a powerful means to treat caloric excess conditions. Important questions remain to be resolved and more clinical research is needed on the long-term effects of SGLT2 inhibition. Potential extrarenal effects need to be explored in order to determine the safety of these compounds. It also remains to be determined whether these drugs lower the toxicity of glucose directly on renal cells, independent of hyperglycemia, which may slow or prevent the progressive nature of diabetic nephropathy.

Topics: Absorption; Benzhydryl Compounds; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Glucose; Glucosides; Humans; Kidney; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

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

The kidney plays a central role in the regulation of plasma glucose levels, although until recently this has not been widely appreciated or considered a target for therapeutic intervention. The sodium glucose co-transporter type 2 (SGLT2) located in the plasma membrane of cells lining the proximal tubule mediates the majority of renal glucose reabsorption from the tubular fluid, which normally prevents the loss of glucose in the urine. Competitive inhibitors of SGLT2 that provoke the renal excretion of glucose have been discovered, thereby providing a unique mechanism to potentially lower the elevated blood glucose levels in patients with diabetes.. To explore the physiology of SGLT2 action and discuss several SGLT2 inhibitors that have entered early clinical development.. All publicly available data were identified by searching the internet for 'SGLT2' and 'SGLT2 inhibitor' through 1 November 2007. Published articles, press releases and abstracts presented at national and international meetings were considered.. Sodium glucose co-transporter type 2 inhibition is a novel treatment option for diabetes, which has been studied in preclinical models and a few potent and selective SGLT2 inhibitors have been reported and are currently in clinical development. These agents appear to be safe and generally well tolerated, and will potentially be a beneficial addition to the growing battery of oral antihyperglycaemic agents.

Topics: Adolescent; Adult; Aged; Benzhydryl Compounds; Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Female; Glucosides; Humans; Hypoglycemic Agents; Male; Middle Aged; Sodium-Glucose Transporter 2 Inhibitors

In the search for potential new drug targets for the treatment of diabetes, sodium-glucose cotransporters (SGLTs), in particular SGLT2, have been the subject of particular attention. SGLT2 plays an important role in glucose reabsorption in the kidney, and SGLT2 inhibitors enhance renal glucose excretion and consequently lower plasma glucose levels. Thus, SGLT2 inhibitors can control energy balance in a negative direction. The principle behind SGLT2 inhibition involves the improvement of diabetic conditions without increasing body weight or the risk of hypoglycemia. A number of pharmaceutical companies are evaluating SGLT2 inhibitors, and studies have confirmed the therapeutic potency and safety of these drugs for the potential treatment of diabetes.

Topics: Animals; Carbonates; Clinical Trials, Phase II as Topic; Diabetes Mellitus, Type 2; Glucosides; Humans; Hypoglycemic Agents; Molecular Structure; Sodium-Glucose Transport Proteins

Sergliflozin, the active entity of sergliflozin etabonate, is a selective inhibitor of sodium-dependent glucose cotransporter 2 (SGLT2). The pharmacokinetics and pharmacodynamics of sergliflozin were evaluated following single oral dose administration of sergliflozin etabonate (5-500 mg) in healthy volunteers (n = 22) and patients with type 2 diabetes mellitus (n = 8). The prodrug was rapidly and extensively converted to sergliflozin; the latter displayed linear kinetics, reached maximum plasma concentrations at approximately 30 to 45 minutes postdose (t(max)), and had a plasma elimination half-life (t(1/2)) of approximately 0.5 to 1 hour. Both prodrug and active entity showed low glomerular filtration and/or extensive renal tubular reabsorption, with <0.5% of the administered dose being recovered in the urine. In both populations, sergliflozin etabonate produced a dose-related glucosuria under fasting conditions and following glucose loading but did not appreciably affect urinary electrolyte excretion or fluid balance. The magnitude and duration of the glucosuric effect closely paralleled plasma sergliflozin concentrations. Sergliflozin did not significantly affect fasting plasma glucose levels but produced transient attenuation of the plasma glucose AUC following glucose challenge. Single doses of sergliflozin etabonate 5 to 500 mg were well tolerated, and there were no clinically significant adverse laboratory findings.

Topics: Administration, Oral; Adolescent; Adult; Area Under Curve; Benzhydryl Compounds; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Monitoring; Female; Glucose; Glucosides; Glycosuria; Humans; Hypoglycemic Agents; Male; Middle Aged; Prodrugs; Water-Electrolyte Balance

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

5a-Carba-β-D-glucopyranose derivatives were synthesized and identified as novel SGLT2-selective inhibitors. These inhibitors exhibited potent SGLT2 inhibition with high selectivity over SGLT1. Among the tested compounds, 6f indicated the most potent hSGLT2 inhibition and the highest selectivity over hSGLT1. Moreover, the pharmacokinetics data also showed that 6h, which had the same aglycon structure as sergliflozin-active (3-active), had a threefold longer half-life time (T(1/2)) than sergliflozin (3) with a high distribution volume in db/db mice. Subsequently, 6h lowered blood glucose levels as much as 3 and showed longer hypoglycemic action than 3 in db/db mice.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Glucose; Male; Mice; Mice, Obese; Molecular Conformation; Molecular Sequence Data; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Stereoisomerism; Structure-Activity Relationship; Tissue Distribution