RESUMEN
A series of 3-aryl-4-isoxazolecarboxamides identified from a high-throughput screening campaign as novel, potent agonists of the human TGR5 G-protein-coupled receptor is described. Many analogues were readily accessible via solution-phase synthesis which resulted in the rapid identification of key structure-activity relationships (SAR), and the discovery of potent exemplars (up to pEC50=9). Details of the SAR and optimization of this series are presented herein.
Asunto(s)
Acrilamidas/síntesis química , Diseño de Fármacos , Isoxazoles/síntesis química , Receptores Acoplados a Proteínas G/agonistas , Acrilamidas/química , Acrilamidas/farmacología , Humanos , Isoxazoles/química , Isoxazoles/farmacología , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A series of 3-aryl-4-isoxazolecarboxamides identified from a high-throughput screening campaign as novel, potent small molecule agonists of the human TGR5 G-protein coupled receptor is described. Subsequent optimization resulted in the rapid identification of potent exemplars 6 and 7 which demonstrated improved GLP-1 secretion in vivo via an intracolonic dose coadministered with glucose challenge in a canine model. These novel TGR5 receptor agonists are potentially useful therapeutics for metabolic disorders such as type II diabetes and its associated complications.