ABSTRACT
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.
Subject(s)
Aniline Compounds/chemistry , Quinolines/chemistry , Receptor, Anaphylatoxin C5a/antagonists & inhibitors , Binding Sites , Chemistry, Pharmaceutical/methods , Drug Design , Humans , Inhibitory Concentration 50 , Ligands , Models, Chemical , Molecular Conformation , Molecular Structure , Structure-Activity RelationshipABSTRACT
A novel series of substituted 2-aryl-5-amino-5,6,7,8-tetrahydroquinoline C5a receptor antagonists is reported. Synthetic routes were developed that allow the substituents on the tetrahydroquinoline core to be efficiently varied, facilitating determination of structure-activity relationships. Members of the series display high binding affinity for the C5a receptor and are potent functional antagonists.
