Discovery of small molecule human C5a receptor antagonists.
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.
Sanganee
Hitesh J
HJ
AstraZeneca R&D Charnwood, Medicinal Chemistry, Bakewell Road, Loughborough, LE11 5RH, UK. Hitesh.sanganee@astrazeneca.com
Baxter
Andrew
A
Barber
Simon
S
Brown
Alastair J H
AJ
Grice
Denise
D
Hunt
Fraser
F
King
Sarah
S
Laughton
David
D
Pairaudeau
Garry
G
Thong
Bob
B
Weaver
Richard
R
Unitt
John
J
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
D000577:Amides; D001555:Benzene Derivatives; C488033:C5AR1 protein, human; D005663:Furans; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement