ABSTRACT
Glucose flux through glucokinase (GK) controls insulin release from the pancreas in response to high levels of glucose. Flux through GK is also responsible for reducing hepatic glucose output. Since many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processes, identifying compounds that can activate GK could provide a therapeutic benefit. Herein we report the further structure activity studies of a novel series of glucokinase activators (GKA). These studies led to the identification of pyridine 72 as a potent GKA that lowered post-prandial glucose in normal C57BL/6J mice, and after 14d dosing in ob/ob mice.
Subject(s)
Enzyme Activators/chemistry , Glucokinase/chemistry , Hypoglycemic Agents/chemistry , Animals , Binding Sites , Blood Glucose/analysis , Crystallography, X-Ray , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Drug Design , Drug Evaluation, Preclinical , Enzyme Activators/metabolism , Enzyme Activators/therapeutic use , Glucokinase/metabolism , Glucose Tolerance Test , Hypoglycemic Agents/metabolism , Hypoglycemic Agents/therapeutic use , Kinetics , Mice , Mice, Inbred C57BL , Molecular Dynamics Simulation , Structure-Activity Relationship , Thiadiazoles/chemistry , Thiadiazoles/metabolismABSTRACT
Benzazole derivatives with a flexible aryl group bonded through a one-atom linker as a new scaffold for a corticotropin-releasing factor 1 (CRF1) receptor antagonist were designed, synthesized, and evaluated. We expected that structural diversity could be expanded beyond that of reported CRF1 receptor antagonists. In a structure-activity relationship study, 4-chloro-N(2)-(4-chloro-2-methoxy-6-methylphenyl)-1-methyl-N(7),N(7)-dipropyl-1H-benzimidazole-2,7-diamine 29g had the most potent binding activity against a human CRF1 receptor and the antagonistic activity (IC50 = 9.5 and 88 nM, respectively) without concerns regarding cytotoxicity at 30 µM. Potent CRF1 receptor-binding activity in brain in an ex vivo test and suppression of stress-induced activation of the hypothalamus-pituitary-adrenocortical (HPA) axis were also observed at 138 µmol/kg of compound 29g after oral administration in mice. Thus, the newly designed benzimidazole 29g showed in vivo CRF1 receptor antagonistic activity and good brain penetration, indicating that it is a promising lead for CRF1 receptor antagonist drug discovery research.
Subject(s)
Benzimidazoles/antagonists & inhibitors , Benzimidazoles/pharmacology , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Adrenocorticotropic Hormone/metabolism , Animals , Brain Chemistry/drug effects , CHO Cells , Cricetinae , Cricetulus , Drug Design , Humans , Hypothalamo-Hypophyseal System/drug effects , Mice , Models, Molecular , Pituitary-Adrenal System/drug effects , Structure-Activity RelationshipABSTRACT
Obesity is characterized by the accumulation of triacylglycerol in adipocytes. Coenzyme A:diacylglycerol acyltransferase 1 (DGAT1) is one of two known DGAT enzymes that catalyze the final and only committed step in triacylglycerol synthesis. In this report, we describe the pharmacological effects of a novel selective DGAT1 inhibitor, Compound-A. This compound inhibited triacylglycerol synthesis in both adipocytes and skeletal myotubes, and increased fatty acid oxidation in skeletal myotubes at 1 µM. The repeated administration of Compound-A to diet-induced obese C57BL/6J and genetically obese KKA(y) mice (3-30 mg/kg for 3-4 weeks) significantly decreased the visceral fat pad weights and the hepatic lipid contents compared to controls without affecting food intake. In addition, fatty acid oxidation in skeletal muscle tissues was increased by the treatment of Compound-A in both mice strains. This is the first report demonstrating that a small synthetic DGAT1 inhibitor increases fatty acid oxidation in skeletal muscle in vitro and ex vivo. These results suggest that DGAT1 inhibition is a promising therapeutic approach for the treatment of obesity and lipid abnormalities such as hepatic steatosis.
Subject(s)
Body Weight/drug effects , Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Lipid Metabolism/drug effects , Niacinamide/analogs & derivatives , Obesity/drug therapy , Pyrazoles/pharmacology , Adipose Tissue/metabolism , Animals , Diacylglycerol O-Acyltransferase/physiology , Dietary Carbohydrates/administration & dosage , Dietary Fats/administration & dosage , Disease Models, Animal , Enzyme Inhibitors/therapeutic use , Liver/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Muscle, Skeletal/metabolism , Niacinamide/pharmacology , Obesity/genetics , Obesity/metabolism , Species Specificity , Triglycerides/metabolismABSTRACT
A series of diacylethylenediamine derivatives were synthesized and evaluated for their inhibitory activity against DGAT-1 and pharmacokinetic profile to discover new small molecule DGAT-1 inhibitors. Among the compounds, N-[2-({[1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]carbonyl}amino)ethyl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide 3x showed potent inhibitory activity and excellent PK profile. Oral administration of 3x to mice with dietary-induced obesity resulted in reduced body weight gain and white adipose tissue weight.
