Optimization of the heterocyclic core of the quinazolinone-derived CXCR3 antagonists.
A series of six-six and six-five fused heterocyclic CXCR3 antagonists has been synthesized and their activities evaluated in an [(125)I]-IP-10 displacement assay and an ITAC mediated in vitro cell migration assay. The pharmacokinetic properties of several top compounds have also been studied. This effort led to the discovery of compounds with increased potency and improved pharmacokinetic properties that could serve as useful tools to study the role of the CXCR3 receptor in vivo.
Li
An-Rong
AR
Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
Johnson
Michael G
MG
Liu
Jiwen
J
Chen
Xiaoqi
X
Du
Xiaohui
X
Mihalic
Jeffrey T
JT
Deignan
Jeffrey
J
Gustin
Darin J
DJ
Duquette
Jason
J
Fu
Zice
Z
Zhu
Liusheng
L
Marcus
Andrew P
AP
Bergeron
Phillipe
P
McGee
Lawrence R
LR
Danao
Jay
J
Lemon
Bryan
B
Carabeo
Teresa
T
Sullivan
Timothy
T
Ma
Ji
J
Tang
Liang
L
Tonn
George
G
Collins
Tassie L
TL
Medina
Julio C
JC
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D052999:Quinazolinones / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D054367:Receptors, CXCR3 / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism
C515187:CXCR3 protein, human; D006571:Heterocyclic Compounds; D052999:Quinazolinones; D054367:Receptors, CXCR3