Evaluation of potent and selective small-molecule antagonists for the CXCR2 chemokine receptor.
N,N'-Diarylureas were prepared, and the structure-activity relationship relative to the CXCR2 receptor was examined. This led to the identification of a potent and highly selective CXCR2 antagonist, which in addition was shown to be functionally active both in vitro against human neutrophils and in vivo in rabbit models of ear edema and neutropenia.
GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, USA. katherine.l.widdowson@gsk.com
Katherine L
KL
Widdowson
John D
JD
Elliott
Daniel F
DF
Veber
Hong
H
Nie
Melvin C
MC
Rutledge
Brent W
BW
McCleland
Jia-Ning
JN
Xiang
Anthony J
AJ
Jurewicz
Robert P
RP
Hertzberg
James J
JJ
Foley
Don E
DE
Griswold
Lenox
L
Martin
Judithann M
JM
Lee
John R
JR
White
Henry M
HM
Sarau
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D054360:Chemokine CXCL1; D018925:Chemokines; D002630:Chemotactic Factors; D002633:Chemotaxis; D006224:Cricetinae; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000139:chemically induced / Q000188:drug therapy; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8; D009503:Neutropenia / Q000139:chemically induced / Q000188:drug therapy; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D011869:Radioligand Assay; D023062:Receptors, Interleukin-8A / Q000037:antagonists & inhibitors / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; C475896:CXCL1 protein, Bos taurus; D054360:Chemokine CXCL1; D018925:Chemokines; D002630:Chemotactic Factors; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8; C483888:N-(3-bromo-4-cyano-2-hydroxyphenyl)-N'-(2-bromophenyl)urea; D010671:Phenylurea Compounds; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D002118:Calcium