Identification of a new class of small molecule C5a receptor antagonists.
C5a is a terminal product of the complement cascade that activates and attracts inflammatory cells including granulocytes, mast cells and macrophages via a specific GPCR, the C5a receptor (C5aR). Inhibition of C5a/C5aR interaction has been shown to be efficacious in several animal models of autoimmune diseases, including RA, SLE and asthma. This account reports the discovery of a new class of C5aR antagonists through high-throughput screening. The lead compounds in this series are selective and block C5a binding, C5a-promoted calcium flux in human neutrophils with nanomolar potency.
Chen
Jack J
JJ
Chemical Sciences, Wyeth Research, Pearl River, NY 10956, USA. chenj24@wyeth.com
Cole
Derek C
DC
Ciszewski
Greg
G
Crouse
Kimberly
K
Ellingboe
John W
JW
Nowak
Pawel
P
Tawa
Gregory J
GJ
Berstein
Gabriel
G
Li
Wei
W
D000818:Animals; D002460:Cell Line; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D008968:Molecular Conformation; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D044087:Receptor, Anaphylatoxin C5a; D013449:Sulfonamides