Synthesis and structure-activity relationships of a series of 3-aryl-4-isoxazolecarboxamides as a new class of TGR5 agonists.
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.
Budzik
Brian W
BW
Discovery Medicinal Chemistry, Discovery Research, GlaxoSmithKline Pharmaceuticals, 1250 South Collegeville Road, PO Box 5089, Collegeville, PA 19426-0989, USA.
Evans
Karen A
KA
Wisnoski
David D
DD
Jin
Jian
J
Rivero
Ralph A
RA
Szewczyk
George R
GR
Jayawickreme
Channa
C
Moncol
David L
DL
Yu
Hongshi
H
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
D000178:Acrylamides; C473772:GPBAR1 protein, human; D007555:Isoxazoles; D043562:Receptors, G-Protein-Coupled