AMG 837: a potent, orally bioavailable GPR40 agonist.
The discovery that certain long chain fatty acids potentiate glucose stimulated insulin secretion through the previously orphan receptor GPR40 sparked interest in GPR40 agonists as potential antidiabetic agents. Optimization of a series of β-substituted phenylpropanoic acids led to the identification of (S)-3-(4-((4'-(trifluoromethyl)biphenyl-3-yl)methoxy)phenyl)hex-4-ynoic acid (AMG 837) as a potent GPR40 agonist with a superior pharmacokinetic profile and robust glucose-dependent stimulation of insulin secretion in rodents.
Amgen Inc. 1120 Veterans Blvd., South San Francisco, CA 94080, USA. jhouze@amgen.com
Jonathan B
JB
Houze
Liusheng
L
Zhu
Ying
Y
Sun
Michelle
M
Akerman
Wei
W
Qiu
Alex J
AJ
Zhang
Rajiv
R
Sharma
Michael
M
Schmitt
Yingcai
Y
Wang
Jiwen
J
Liu
Jinqian
J
Liu
Julio C
JC
Medina
Jeff D
JD
Reagan
Jian
J
Luo
George
G
Tonn
Jane
J
Zhang
Jenny Ying-Lin
JY
Lu
Michael
M
Chen
Edwin
E
Lopez
Kathy
K
Nguyen
Li
L
Yang
Liang
L
Tang
Hui
H
Tian
Steven J
SJ
Shuttleworth
Daniel C-H
DC
Lin
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000172:deficiency / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000480:Alkynes; D010666:Phenylpropionates
D001713:Biphenyl Compounds; D043562:Receptors, G-Protein-Coupled; C473036:Ffar1 protein, mouse; C557933:AMG-837; D000480:Alkynes; D010666:Phenylpropionates