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
The optimization of a series of benzimidazole glucokinase activators is described. We identified a novel and potent achiral benzimidazole derivative as an allosteric GK activator. This activator was designed and synthesized via removal of the chiral center of the lead compound, 6-(N-acylpyrrolidin-2-yl)benzimidazole. The activator exhibited good PK profiles in rats and dogs, and significant hypoglycemic efficacy at 1 mg/kg po dosing in a rat OGTT model. The binding site and binding mode of the benzimidazole class of GKA with GK protein was confirmed by X-ray crystallographic analysis.
Subject(s)
Benzimidazoles/chemical synthesis , Glucokinase/drug effects , Allosteric Regulation/drug effects , Animals , Benzimidazoles/pharmacology , Binding Sites , Crystallography, X-Ray , Dogs , Drug Design , Hypoglycemic Agents/chemical synthesis , RatsABSTRACT
The synthesis and structure-activity-relationships (SARs) of novel 2-(pyridine-2-yl)-1H-benzimidazole glucokinase activators are described. Systematic modification of benzimidazole lead 5a identified from a high-throughput screening led to the discovery of a potent and metabolically stable glucokinase activator 16p(R) with greater structural diversity from GKAs reported to date. The compound also demonstrated acute oral glucose lowering efficacy in rat OGTT model.
Subject(s)
Benzimidazoles/chemical synthesis , Glucokinase/metabolism , Allosteric Site , Animals , Benzimidazoles/pharmacology , Binding Sites , Chemistry, Pharmaceutical/methods , Diabetes Mellitus, Experimental/drug therapy , Drug Design , Enzyme Activation , Glucose Tolerance Test , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacology , Models, Chemical , Molecular Conformation , Rats , Structure-Activity RelationshipABSTRACT
The optimization of our lead GK activator 2a to 3-[(1S)-2-hydroxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]-N-1,3-thiazol-2-ylbenzamide (6g), a potent GK activator with good oral availability, is described, including to uncouple the relationship between potency and hydrophobicity. Following oral administration, this compound exhibited robust glucose lowering in diabetic model rodents.
