Discovery and optimization of CRTH2 and DP dual antagonists.
A series of phenylacetic acid derivatives was discovered as CRTH2 antagonists. Modification of the series led to compounds that are also antagonists of DP. Since activation of CRTH2 and DP are believed to play key roles in mediating responses of asthma and other immune diseases, this series was optimized to increase the dual antagonistic activities and improve pharmacokinetic properties. These efforts led to selection of AMG 009 as a clinical candidate.
Liu
Jiwen
J
Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA. jiwenl@amgen.com
Fu
Zice
Z
Wang
Yingcai
Y
Schmitt
Mike
M
Huang
Alan
A
Marshall
Derek
D
Tonn
George
G
Seitz
Lisa
L
Sullivan
Tim
T
Lucy Tang
H
H
Collins
Tassie
T
Medina
Julio
J
D000818:Animals; D001249:Asthma / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D011982:Receptors, Prostaglandin / Q000737:chemistry* / Q000145:classification; D013329:Structure-Activity Relationship; D018418:Th2 Cells / Q000378:metabolism
D011982:Receptors, Prostaglandin