RESUMEN
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.
Asunto(s)
Bencimidazoles/síntesis química , Glucoquinasa/metabolismo , Sitio Alostérico , Animales , Bencimidazoles/farmacología , Sitios de Unión , Química Farmacéutica/métodos , Diabetes Mellitus Experimental/tratamiento farmacológico , Diseño de Fármacos , Activación Enzimática , Prueba de Tolerancia a la Glucosa , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacología , Modelos Químicos , Conformación Molecular , Ratas , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Receptores de Neuropéptido Y/antagonistas & inhibidores , Administración Oral , Bencimidazoles/química , Encéfalo/efectos de los fármacos , Técnicas Químicas Combinatorias , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Relación Estructura-ActividadRESUMEN
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).