title: Identification of a new class of small molecule C5a receptor antagonists.
abstract: 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.
authors.affiliation: Chemical Sciences, Wyeth Research, Pearl River, NY 10956, USA. chenj24@wyeth.com
authors.forename: Jack J
authors.initials: JJ
authors.lastname: Chen
authors.forename: Derek C
authors.initials: DC
authors.lastname: Cole
authors.forename: Greg
authors.initials: G
authors.lastname: Ciszewski
authors.forename: Kimberly
authors.initials: K
authors.lastname: Crouse
authors.forename: John W
authors.initials: JW
authors.lastname: Ellingboe
authors.forename: Pawel
authors.initials: P
authors.lastname: Nowak
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Tawa
authors.forename: Gabriel
authors.initials: G
authors.lastname: Berstein
authors.forename: Wei
authors.initials: W
authors.lastname: Li
mesh_terms: 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
chemical_list: D044087:Receptor, Anaphylatoxin C5a; D013449:Sulfonamides