Exploration of phenylpropanoic acids as agonists of the free fatty acid receptor 4 (FFA4): Identification of an orally efficacious FFA4 agonist.
The long chain free fatty acid receptor 4 (FFA4/GPR120) has recently been recognized as lipid sensor playing important roles in nutrient sensing and inflammation and thus holds potential as a therapeutic target for type 2 diabetes and metabolic syndrome. To explore the effects of stimulating this receptor in animal models of metabolic disease, we initiated work to identify agonists with appropriate pharmacokinetic properties to support progression into in vivo studies. Extensive SAR studies of a series of phenylpropanoic acids led to the identification of compound 29, a FFA4 agonist which lowers plasma glucose in two preclinical models of type 2 diabetes.
GlaxoSmithKline, Enteroendocrine Discovery Performance Unit and Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, United States. Electronic address: ssparks@viamet.com.
Steven M
SM
Sparks
GlaxoSmithKline, Enteroendocrine Discovery Performance Unit and Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, United States.
Christopher
C
Aquino
GlaxoSmithKline, Enteroendocrine Discovery Performance Unit and Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, United States.
Pierette
P
Banker
GlaxoSmithKline, Enteroendocrine Discovery Performance Unit and Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, United States.
Jon L
JL
Collins
GlaxoSmithKline, Enteroendocrine Discovery Performance Unit and Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, United States.
David
D
Cowan
GlaxoSmithKline, Enteroendocrine Discovery Performance Unit and Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, United States.
Caroline
C
Diaz
GlaxoSmithKline, Enteroendocrine Discovery Performance Unit and Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, United States.
Steven T
ST
Dock
GlaxoSmithKline, Enteroendocrine Discovery Performance Unit and Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, United States.
Donald L
DL
Hertzog
GlaxoSmithKline, Enteroendocrine Discovery Performance Unit and Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, United States.
Xi
X
Liang
GlaxoSmithKline, Enteroendocrine Discovery Performance Unit and Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, United States.
Erin D
ED
Swiger
GlaxoSmithKline, Enteroendocrine Discovery Performance Unit and Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, United States.
Josephine
J
Yuen
GlaxoSmithKline, Enteroendocrine Discovery Performance Unit and Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, United States.
Grace
G
Chen
GlaxoSmithKline, Enteroendocrine Discovery Performance Unit and Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, United States.
Channa
C
Jayawickreme
GlaxoSmithKline, Enteroendocrine Discovery Performance Unit and Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, United States.
David
D
Moncol
GlaxoSmithKline, Enteroendocrine Discovery Performance Unit and Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, United States.
Christopher
C
Nystrom
GlaxoSmithKline, Enteroendocrine Discovery Performance Unit and Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, United States.
Vincent
V
Rash
GlaxoSmithKline, Enteroendocrine Discovery Performance Unit and Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, United States.
Thomas
T
Rimele
GlaxoSmithKline, Enteroendocrine Discovery Performance Unit and Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, United States.
Shane
S
Roller
GlaxoSmithKline, Enteroendocrine Discovery Performance Unit and Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, United States.
Sean
S
Ross
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D010666:Phenylpropionates / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
D001786:Blood Glucose; C498007:FFAR4 protein, mouse; D010666:Phenylpropionates; D043562:Receptors, G-Protein-Coupled
Free fatty acid receptor 1; Free fatty acid receptor 4; GPR120; Phenylpropanoic acid; Type 2 diabetes