Discovery of 3-aryl-4-isoxazolecarboxamides as TGR5 receptor agonists.
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.
Evans
Karen A
KA
Discovery Research, GlaxoSmithKline Pharmaceuticals, Collegeville, PA 19426-0989, USA. karen.a.evans@gsk.com
Budzik
Brian W
BW
Ross
Sean A
SA
Wisnoski
David D
DD
Jin
Jian
J
Rivero
Ralph A
RA
Vimal
Mythily
M
Szewczyk
George R
GR
Jayawickreme
Channa
C
Moncol
David L
DL
Rimele
Thomas J
TJ
Armour
Susan L
SL
Weaver
Susan P
SP
Griffin
Robert J
RJ
Tadepalli
Sarva M
SM
Jeune
Michael R
MR
Shearer
Todd W
TW
Chen
Zibin B
ZB
Chen
Lihong
L
Anderson
Donald L
DL
Becherer
J David
JD
De Los Frailes
Maite
M
Colilla
Francisco Javier
FJ
D000577:Amides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D005947:Glucose / Q000008:administration & dosage; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*
D000577:Amides; C473772:GPBAR1 protein, human; D007555:Isoxazoles; D043562:Receptors, G-Protein-Coupled; D052216:Glucagon-Like Peptide 1; D005947:Glucose