title: Discovery of 3-aryl-4-isoxazolecarboxamides as TGR5 receptor agonists.
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 receptor agonists are potentially useful therapeutics for metabolic disorders such as type II diabetes and its associated complications.
authors.affiliation: Discovery Research, GlaxoSmithKline Pharmaceuticals, Collegeville, PA 19426-0989, USA. karen.a.evans@gsk.com
authors.forename: Karen A
authors.initials: KA
authors.lastname: Evans
authors.forename: Brian W
authors.initials: BW
authors.lastname: Budzik
authors.forename: Sean A
authors.initials: SA
authors.lastname: Ross
authors.forename: David D
authors.initials: DD
authors.lastname: Wisnoski
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Rivero
authors.forename: Mythily
authors.initials: M
authors.lastname: Vimal
authors.forename: George R
authors.initials: GR
authors.lastname: Szewczyk
authors.forename: Channa
authors.initials: C
authors.lastname: Jayawickreme
authors.forename: David L
authors.initials: DL
authors.lastname: Moncol
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rimele
authors.forename: Susan L
authors.initials: SL
authors.lastname: Armour
authors.forename: Susan P
authors.initials: SP
authors.lastname: Weaver
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Griffin
authors.forename: Sarva M
authors.initials: SM
authors.lastname: Tadepalli
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jeune
authors.forename: Todd W
authors.initials: TW
authors.lastname: Shearer
authors.forename: Zibin B
authors.initials: ZB
authors.lastname: Chen
authors.forename: Lihong
authors.initials: L
authors.lastname: Chen
authors.forename: Donald L
authors.initials: DL
authors.lastname: Anderson
authors.forename: J David
authors.initials: JD
authors.lastname: Becherer
authors.forename: Maite
authors.initials: M
authors.lastname: De Los Frailes
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Colilla
mesh_terms: 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*
chemical_list: D000577:Amides; C473772:GPBAR1 protein, human; D007555:Isoxazoles; D043562:Receptors, G-Protein-Coupled; D052216:Glucagon-Like Peptide 1; D005947:Glucose