Discovery of potent and orally bioavailable N,N'-diarylurea antagonists for the CXCR2 chemokine receptor.
A series of 3-substituted N,N'-diarylureas was prepared and the structure-activity relationship relative to CXCR2 receptor affinity as well as their pharmacokinetic properties were examined. In vitro microsomal metabolism studies indicated that the lower clearance rates of the 3-sulfonamido-substituted compounds were most likely due to the suppression of glucuronidation.
Jin
Qi
Q
GlaxoSmithKline, PO Box 1539, King of Prussia, PA 19406-0939, USA.
Nie
Hong
H
McCleland
Brent W
BW
Widdowson
Katherine L
KL
Palovich
Michael R
MR
Elliott
John D
JD
Goodman
Richard M
RM
Burman
Miriam
M
Sarau
Henry M
HM
Ward
Keith W
KW
Nord
Melanie
M
Orr
Bonnie M
BM
Gorycki
Peter D
PD
Busch-Petersen
Jakob
J
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013453:Sulfonylurea Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
D023063:Receptors, Interleukin-8B; D013453:Sulfonylurea Compounds