canagliflozin 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

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

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

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