III. Identification of novel CXCR3 chemokine receptor antagonists with a pyrazinyl-piperazinyl-piperidine scaffold.
The SAR of a novel pyrazinyl-piperazinyl-piperidine scaffold with CXCR3 receptor antagonist activity was explored. Optimization of the DMPK profile and reduction of hERG inhibition is described. Compound 16e with single-digit CXCR3 affinity, good rat PK and hERG profiles has been identified as a lead for further study.
Merck Research Laboratories, Kenilworth, NJ 07033, USA. seong.heon.kim@merck.com
Seong Heon
SH
Kim
Gopinadhan N
GN
Anilkumar
Lisa Guise
LG
Zawacki
Qingbei
Q
Zeng
De-Yi
DY
Yang
Yuefei
Y
Shao
Guizhen
G
Dong
Xiaolian
X
Xu
Wensheng
W
Yu
Yueheng
Y
Jiang
Chung-Her
CH
Jenh
James W
JW
Hall
Carolyn Diianni
CD
Carroll
Doug W
DW
Hobbs
John J
JJ
Baldwin
Brian F
BF
McGuinness
Stuart B
SB
Rosenblum
Joseph A
JA
Kozlowski
Bandarpalle B
BB
Shankar
Neng-Yang
NY
Shih
D000818:Animals; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011719:Pyrazines / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D054367:Receptors, CXCR3 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D010879:Piperazines; D011719:Pyrazines; D054367:Receptors, CXCR3