Design and optimization of aniline-substituted tetrahydroquinoline C5a receptor antagonists.
A series of aniline-substituted tetrahydroquinoline C5a receptor antagonists were discovered. A functionality requirement of ortho substitution on the aniline was revealed. Secondary anilines, in general, outperformed tertiary analogs in inhibition of C5a-induced calcium mobilization. Further enhancement of activity was realized in the presence of an ortho hydroxyalkyl side chain. The functional IC(50) of selected analogs was optimized to the single-digit nanomolar level.
Gong
Yong
Y
Johnson & Johnson Pharmaceutical Research and Development, Spring House, PA 19477-0776, USA. ygong@prdus.jnj.com
Barbay
J Kent
JK
Buntinx
Mieke
M
Li
Jian
J
Wauwe
Jean Van
JV
Claes
Concha
C
Lommen
Guy Van
GV
Hornby
Pamela J
PJ
He
Wei
W
D000814:Aniline Compounds / Q000737:chemistry*; D001665:Binding Sites; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008956:Models, Chemical; D008968:Molecular Conformation; D015394:Molecular Structure; D011804:Quinolines / Q000737:chemistry*; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D000814:Aniline Compounds; D008024:Ligands; D011804:Quinolines; D044087:Receptor, Anaphylatoxin C5a; C023650:aniline