ABSTRACT
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
Design, syntheses, and structure-activity relationships of a novel class of 2-{3-oxospiro[isobenzofuran-1(3H),4'-piperidin]-1'-yl}benzimidazole NPY Y5 receptor antagonists are described. The benzimidazole structures were newly designed based on the urea linkage of our prototype Y5 receptor antagonists (2 and 3). By optimizing substituents on the benzimidazole core part of the lead compound 5a, we were able to develop a potent, orally available, and brain-penetrable Y5 selective antagonist (5k).
Subject(s)
Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Receptors, Neuropeptide Y/antagonists & inhibitors , Administration, Oral , Animals , Benzimidazoles/chemistry , Brain/drug effects , Combinatorial Chemistry Techniques , Drug Design , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
Syntheses and structure-activity relationships of a novel class of 2-[3-oxospiro[isobenzofuran-1(3H),1'-cyclohexan]-4'-yl]benzimidazole NPY Y5 receptor antagonists are described. Optimization of the lead compound 2a by incorporating substituents into the 5-position or into both the 5- and 6-positions of the benzimidazole core part led to the identification of 5-(5-methyl-1,2,4-oxadiazol-2-yl)benzimidazole (2r: IC(50)=3.3 nM) and 5-(2-methyltetrazol-5-yl)benzimidazole (2u: IC(50)=5.9 nM), both of which are potent, selective, and orally bioavailable Y5 receptor antagonists.
