ipragliflozin 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

The pharmacological profile of ipragliflozin (ASP1941; (1S)-1,5-anhydro-1-C-{3-[(1-benzothiophen-2-yl)methyl]-4-fluorophenyl}-D: -glucitol compound with L: -proline (1:1)), a novel SGLT2 selective inhibitor, was investigated. In vitro, the potency of ipragliflozin to inhibit SGLT2 and SGLT1 and stability were assessed. In vivo, the pharmacokinetic and pharmacologic profiles of ipragliflozin were investigated in normal mice, streptozotocin-induced type 1 diabetic rats, and KK-A(y) type 2 diabetic mice. Ipragliflozin potently and selectively inhibited human, rat, and mouse SGLT2 at nanomolar ranges and exhibited stability against intestinal glucosidases. Ipragliflozin showed good pharmacokinetic properties following oral dosing, and dose-dependently increased urinary glucose excretion, which lasted for over 12 h in normal mice. Single administration of ipragliflozin resulted in dose-dependent and sustained antihyperglycemic effects in both diabetic models. In addition, once-daily ipragliflozin treatment over 4 weeks improved hyperglycemia with a concomitant increase in urinary glucose excretion in both diabetic models. In contrast, ipragliflozin at pharmacological doses did not affect normoglycemia, as was the case with glibenclamide, and did not influence intestinal glucose absorption and electrolyte balance. These results suggest that ipragliflozin is an orally active SGLT2 selective inhibitor that induces sustained increases in urinary glucose excretion by inhibiting renal glucose reabsorption, with subsequent antihyperglycemic effect and a low risk of hypoglycemia. Ipragliflozin has, therefore, the therapeutic potential to treat hyperglycemia in diabetes by increasing glucose excretion into urine.

Topics: Animals; Blood Glucose; Carbohydrate Metabolism; CHO Cells; Cricetinae; Cricetulus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Gastrointestinal Tract; Glucosides; Humans; Hypoglycemic Agents; Insulin; Male; Mice; Mice, Inbred ICR; Phlorhizin; Rats; Rats, Sprague-Dawley; Sodium-Glucose Transporter 1; Sodium-Glucose Transporter 2 Inhibitors; Thiophenes

A series of C-glucosides with various heteroaromatics has been synthesized and its inhibitory activity toward SGLTs was evaluated. Upon screening several compounds, the benzothiophene derivative (14a) was found to have potent inhibitory activity against SGLT2 and good selectivity versus SGLT1. Through further optimization of 14a, a novel benzothiophene derivative (14h; ipragliflozin, ASP1941) was discovered as a highly potent and selective SGLT2 inhibitor that reduced blood glucose levels in a dose-dependent manner in diabetic models KK-A(y) mice and STZ rats.

Topics: Animals; Blood Glucose; CHO Cells; Cricetinae; Diabetes Mellitus, Type 2; Disease Models, Animal; Dose-Response Relationship, Drug; Glucosides; Humans; Hypoglycemic Agents; Inhibitory Concentration 50; Male; Mice; Molecular Structure; Rats; Rats, Sprague-Dawley; Sodium-Glucose Transporter 2 Inhibitors; Thiophenes