Discovery of 3-aryl-4-isoxazolecarboxamides as TGR5 receptor agonists

…, M Vimal, GR Szewczyk, C Jayawickreme…

Index: Evans, Karen A.; Budzik, Brian W.; Ross, Sean A.; Wisnoski, David D.; Jin, Jian; Rivero, Ralph A.; Vimal, Mythily; Szewczyk, George R.; Jayawickreme, Channa; Moncol, David L.; Rimele, Thomas J.; Armour, Susan L.; Weaver, Susan P.; Griffin, Robert J.; Tadepalli, Sarva M.; Jeune, Michael R.; Shearer, Todd W.; Chen, Zibin B.; Chen, Lihong; Anderson, Donald L.; Becherer, J. David; De Los Frailes, Maite; Colilla, Francisco Javier Journal of Medicinal Chemistry, 2009 , vol. 52, # 24 p. 7962 - 7965

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Citation Number: 51

Abstract

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 ...