title: Synthesis and structure-activity relationships of a series of 3-aryl-4-isoxazolecarboxamides as a new class of TGR5 agonists.
abstract: A series of 3-aryl-4-isoxazolecarboxamides identified from a high-throughput screening campaign as novel, potent agonists of the human TGR5 G-protein-coupled receptor is described. Many analogues were readily accessible via solution-phase synthesis which resulted in the rapid identification of key structure-activity relationships (SAR), and the discovery of potent exemplars (up to pEC50=9). Details of the SAR and optimization of this series are presented herein.
authors.affiliation: Discovery Medicinal Chemistry, Discovery Research, GlaxoSmithKline Pharmaceuticals, 1250 South Collegeville Road, PO Box 5089, Collegeville, PA 19426-0989, USA.
authors.forename: Brian W
authors.initials: BW
authors.lastname: Budzik
authors.forename: Karen A
authors.initials: KA
authors.lastname: Evans
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: 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: Hongshi
authors.initials: H
authors.lastname: Yu
mesh_terms: D000178:Acrylamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D000178:Acrylamides; C473772:GPBAR1 protein, human; D007555:Isoxazoles; D043562:Receptors, G-Protein-Coupled