RESUMO
Modulation of gastrointestinal nutrient sensing pathways provides a promising a new approach for the treatment of metabolic diseases including diabetes and obesity. The calcium-sensing receptor has been identified as a key receptor involved in mineral and amino acid nutrient sensing and thus is an attractive target for modulation in the intestine. Herein we describe the optimization of gastrointestinally restricted calcium-sensing receptor agonists starting from a 3-aminopyrrolidine-containing template leading to the identification of GI-restricted agonist 19 (GSK3004774).
Assuntos
Receptores de Detecção de Cálcio/agonistas , Animais , Cálcio/metabolismo , Permeabilidade da Membrana Celular/efeitos dos fármacos , Cães , Trato Gastrointestinal/metabolismo , Células HEK293 , Humanos , Células Madin Darby de Rim Canino , Pirrolidinas/química , Pirrolidinas/metabolismo , Pirrolidinas/farmacologia , Receptores de Detecção de Cálcio/genética , Receptores de Detecção de Cálcio/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
