sergliflozin-etabonate and Hyperglycemia

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

Sodium glucose co-transporter 1 (SGLT1) plays a dominant role in the absorption of glucose in the gut and is considered a promising target in the development of treatments for postprandial hyperglycemia. A series of 4-benzyl-1H-pyrazol-3-yl β-d-glucopyranoside derivatives have been synthesized, and its inhibitory activity toward SGLTs has been evaluated. By altering the substitution groups at the 5-position of the pyrazole ring, and every position of the phenyl ring, we studied the structure-activity relationship (SAR) profiles and identified a series of potent and selective SGLT1 inhibitors. Representative derivatives showed a dose-dependent suppressing effect on the escalation of blood glucose levels in oral mixed carbohydrate tolerance tests (OCTT) in streptozotocin-nicotinamide-induced diabetic rats (NA-STZ rats).

Topics: Animals; Blood Glucose; Crystallography, X-Ray; Diabetes Mellitus, Experimental; Glucosides; Humans; Hyperglycemia; Hypoglycemic Agents; Molecular Conformation; Rats; Sodium-Glucose Transporter 1; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Structure-Activity Relationship