ABSTRACT
Sodium-dependent glucose co-transporter 2 (SGLT2) inhibition has been demonstrated to efficiently control hyperglycemia via an insulin secretion-independent pathway. The unique mode of action eliminates the risk of hypoglycemia and makes SGLT2 inhibitors an attractive option for the treatment of type 2 diabetes. In a continuation of our previous studies on SGLT2 inhibitors bearing different sugar moieties, sixteen new N-glucosyl indole derivatives were designed, synthesized, and evaluated for their inhibitory activity against hSGLT2. Of these sixteen, acethydrazide-containing N-glucosyl indole 9d was found to be the most potent SGLT2 inhibitor, and caused a significant elevation in urine glucose excretion in rats at 50â¯mg/kg, relative to the vehicle control.
Subject(s)
Glucosides/pharmacology , Indoles/pharmacology , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Sodium-Glucose Transporter 2/metabolism , Animals , Benzhydryl Compounds/pharmacology , CHO Cells , Cricetulus , Glucosides/chemical synthesis , Glucosides/chemistry , Glucosides/pharmacokinetics , Humans , Indoles/chemical synthesis , Indoles/chemistry , Indoles/pharmacokinetics , Molecular Structure , Rats, Sprague-Dawley , Sodium-Glucose Transporter 2 Inhibitors/chemical synthesis , Sodium-Glucose Transporter 2 Inhibitors/chemistry , Sodium-Glucose Transporter 2 Inhibitors/pharmacokinetics , Structure-Activity RelationshipABSTRACT
Humans have two glutaminase genes, GLS (GLS1) and GLS2, each of which has two alternative transcripts: the kidney isoform (KGA) and glutaminase C (GAC) for GLS, and the liver isoform (LGA) and glutaminase B (GAB) for GLS2. Initial hit compound (Z)-5-((1-(4-bromophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)methylene)thiazolidine-2,4-dione (2), a thiazolidine-2,4-dione, was obtained from a high throughput screening of 40â¯000 compounds against KGA. Subsequently, a series of thiazolidine-2,4-dione derivatives was synthesized. Most of these were found to inhibit KGA and GAC with comparable activities, were less potent inhibitors of GAB, and were moderately selective for GLS1 over GLS2. The relationships between chemical structure, activity, and selectivity were investigated. The lead compounds obtained were found to (1) offer in vitro cellular activities for inhibiting cell growth, clonogenicity, and cellular glutamate production, (2) exhibit high concentrations of exposure in plasma by a pharmacokinetic study, and (3) reduce the tumor size of xenografted human pancreatic AsPC-1 carcinoma cells in mice.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Glutaminase/antagonists & inhibitors , Thiazolidinediones/chemistry , Thiazolidinediones/pharmacology , Animals , Antineoplastic Agents/blood , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Design , Enzyme Inhibitors/blood , Enzyme Inhibitors/therapeutic use , Glutaminase/metabolism , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Models, Molecular , Pancreas/drug effects , Pancreas/metabolism , Pancreas/pathology , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Rats , Rats, Sprague-Dawley , Thiazolidinediones/blood , Thiazolidinediones/therapeutic useABSTRACT
Suppression of glucose reabsorption through the inhibition of sodium-dependent glucose co-transporter 2 (SGLT2) is a promising therapeutic approach for the treatment of type 2 diabetes. To investigate the effect of C6-substitution on inhibition of SGLT2 by N-indolylglucosides, a small library of 6-triazole, 6-amide, 6-urea, and 6-thiourea N-indolylglycosides were synthesized and tested. A detailed structure-activity relationship (SAR) study culminated in the identification of 6-amide derivatives 6a and 6o as potent SGLT2 inhibitors, which were further tested for inhibitory activity against SGLT1. The data obtained indicated that 6a and 6o are mildly to moderately selective for SGLT2 over SGLT1. Both compounds were also evaluated in a urinary glucose excretion test and pharmacokinetic study; 6a was found capable of inducing urinary glucose excretion in normal SD rats.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Glycosides/chemistry , Glycosides/pharmacology , Sodium-Glucose Transporter 2 Inhibitors , Animals , CHO Cells , Cricetulus , Diabetes Mellitus, Type 2/metabolism , Glucose/metabolism , Glycosides/pharmacokinetics , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Rats, Sprague-Dawley , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacokinetics , Small Molecule Libraries/pharmacology , Sodium-Glucose Transporter 2/metabolismABSTRACT
A novel series of N-linked ß-D-xylosides were synthesized and evaluated for inhibitory activity against sodium-dependent glucose cotransporter 2 (SGLT2) in a cell-based assay. Of these, the 4-chloro-3-(4-cyclopropylbenzyl)-1-(ß-D-xylopyranosyl)-1H-indole 19m was found to be the most potent inhibitor, with an EC(50) value similar to that of the natural SGLT2 inhibitor phlorizin. Further studies in Sprague-Dawley (SD) rats indicated that 19m significantly increased urine glucose excretion in a dose-dependent manner with oral administration. The antihyperglycemic effect of 19m was also observed in streptozotocin (STZ) induced diabetic SD rats. These results described here are a good starting point for further investigations into N-glycoside SGLT2 inhibitors.
