1-5-anhydro-1-(5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl)-1-thioglucitol 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; 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

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