ABSTRACT
We describe design, syntheses and structure-activity relationships of a novel class of 4,6-disubstituted quinazoline glucokinase activators. Prototype quinazoline leads (4 and 5) were designed based on the X-ray analyses of the previous 2-aminobenzamide lead classes. Modifications of the quinazoline leads led to the identification of a potent GK activator (21d).
Subject(s)
Glucokinase/chemistry , Hypoglycemic Agents/chemistry , Quinazolines/chemistry , Animals , Blood Glucose/analysis , Drug Discovery , Glucokinase/metabolism , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacology , Mice , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Glucagon-like peptide-1 (GLP-1) is an incretin hormone that potentiates insulin secretion in a glucose-dependent manner. Selective GLP-1 secretagogue would be one of the potential therapeutic targets for type 2 diabetes. Here, we describe a newly identified small molecule compound (compound A) that stimulates secretion of GLP-1 in murine enteroendocrine cell lines, STC-1 and GLUTag cells, and in primary cultured fetal rat intestinal cells (FRIC). The underlying mechanism by which compound A stimulated GLP-1 secretion was also examined. Compound A stimulated GLP-1 secretion from STC-1 cells in a concentration-dependent manner, and also from GLUTag cells and FRIC. The action of compound A was selective against other tested endocrine functions such as secretion of insulin from rat islets, growth hormone from rat pituitary gland cells, and norepinephrine from rat PC-12 cells. In STC-1 cells, the compound A-stimulated GLP-1 secretion was neither due to cyclic AMP production nor to Ca(2+) release from intracellular stores, but to extracellular Ca(2+) influx. The response was inhibited by the presence of either L-type Ca(2+) channel blockers or K(+) ionophore. Perforated-patch clamp study revealed that compound A induces membrane depolarization. These results suggest that neither Galphas- nor Galphaq-coupled signaling account for the mechanism of action, but depolarization-coupled Ca(2+) influx from extracellular space is the primary cause for the GLP-1 secretion stimulated by compound A. Identifying a specific target molecule for compound A will reveal a selective regulatory pathway that leads to depolarization-mediated GLP-1 secretion.
Subject(s)
Calcium Channel Agonists/pharmacology , Calcium/metabolism , Glucagon-Like Peptide 1/metabolism , Membrane Potentials/drug effects , Secretory Pathway/drug effects , Animals , Calcium/physiology , Calcium Channel Blockers/pharmacology , Cells, Cultured , Drug Evaluation, Preclinical , Enteroendocrine Cells/drug effects , Enteroendocrine Cells/metabolism , Female , Isoindoles/pharmacology , Male , Membrane Potentials/physiology , Mice , Oxazoles/pharmacology , PC12 Cells , Pregnancy , Rats , Rats, Wistar , Substrate Specificity , Verapamil/pharmacologyABSTRACT
A novel class of 3,6-disubstituted 2-pyridinecarboxamide derivatives was designed based on X-ray analysis of the 2-aminobenzamide lead class. Subsequent chemical modification led to the discovery of potent GK activators which eliminate potential toxicity concerns associated with an aniline group of the lead structure. Compound 7 demonstrated glucose lowering effect in a rat OGTT model.
Subject(s)
Amides/chemistry , Glucokinase/metabolism , Hypoglycemic Agents/chemistry , Pyridines/chemistry , Amides/chemical synthesis , Amides/pharmacokinetics , Animals , Crystallography, X-Ray , Disease Models, Animal , Drug Discovery , Glucokinase/chemistry , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacokinetics , Pyridines/chemical synthesis , Pyridines/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
The identification and structure-activity-relationships (SARs) of novel 2-amino benzamide glucokinase activators are described. Compounds in this series were developed to be potent GK activators, and their binding mode to the GK protein was determined by crystal structure analysis. In vivo pharmacokinetic and acute in vivo efficacy studies of compound 18 are also described.
