title: Discovery of small molecule human C5a receptor antagonists.
abstract: A novel series of small molecule C5a antagonists is reported. In particular, in vitro metabolic studies and solution based combinatorial synthesis are demonstrated as useful tools for the rapid identification of antagonists with low in vitro clearance. Members of this series specifically inhibited the binding of (125)I-labeled C5a to human recombinant C5a receptor (C5aR). In functional cell assays these compounds displayed surmountable antagonism against C5a and did not demonstrate any detectable agonist activity.
authors.affiliation: AstraZeneca R&D Charnwood, Medicinal Chemistry, Bakewell Road, Loughborough, LE11 5RH, UK. Hitesh.sanganee@astrazeneca.com
authors.forename: Hitesh J
authors.initials: HJ
authors.lastname: Sanganee
authors.forename: Andrew
authors.initials: A
authors.lastname: Baxter
authors.forename: Simon
authors.initials: S
authors.lastname: Barber
authors.forename: Alastair J H
authors.initials: AJ
authors.lastname: Brown
authors.forename: Denise
authors.initials: D
authors.lastname: Grice
authors.forename: Fraser
authors.initials: F
authors.lastname: Hunt
authors.forename: Sarah
authors.initials: S
authors.lastname: King
authors.forename: David
authors.initials: D
authors.lastname: Laughton
authors.forename: Garry
authors.initials: G
authors.lastname: Pairaudeau
authors.forename: Bob
authors.initials: B
authors.lastname: Thong
authors.forename: Richard
authors.initials: R
authors.lastname: Weaver
authors.forename: John
authors.initials: J
authors.lastname: Unitt
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D004285:Dogs; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D001555:Benzene Derivatives; C488033:C5AR1 protein, human; D005663:Furans; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement