ABSTRACT
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).
Subject(s)
Receptors, Calcium-Sensing/agonists , Animals , Calcium/metabolism , Cell Membrane Permeability/drug effects , Dogs , Gastrointestinal Tract/metabolism , HEK293 Cells , Humans , Madin Darby Canine Kidney Cells , Pyrrolidines/chemistry , Pyrrolidines/metabolism , Pyrrolidines/pharmacology , Receptors, Calcium-Sensing/genetics , Receptors, Calcium-Sensing/metabolism , Structure-Activity RelationshipABSTRACT
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.
