ABSTRACT
The synthesis and in vitro binding of several new arginine-containing C3aR ligands are reported. DMPK properties and functional activities of selected compounds have been evaluated. One compound is shown to be active in an in vivo model of airway inflammation after aerosol administration.
Subject(s)
Arginine/pharmacology , Complement Activation/drug effects , Membrane Proteins/metabolism , Receptors, Complement/metabolism , Aerosols/administration & dosage , Animals , Arginine/analogs & derivatives , Arginine/chemical synthesis , Inflammation/chemically induced , Inflammation/pathology , Ligands , Mice , Mice, Inbred BALB C , Models, Biological , Protein Binding , Protein Serine-Threonine Kinases/metabolism , Respiratory Mucosa/pathology , Structure-Activity Relationship , Time FactorsABSTRACT
The synthesis and structure-activity relationships against the C3a receptor of a series of substituted aminopiperidine derivatives are reported. DMPK properties and functional activities of selected compounds are described. The compounds obtained are the first non-arginine ligands of C3aR.
Subject(s)
Amines/chemistry , Complement Activation/drug effects , Membrane Proteins/metabolism , Piperidines/pharmacology , Receptors, Complement/metabolism , Animals , Ligands , Mice , Mice, Inbred BALB C , Piperidines/chemical synthesis , Protein Binding , Protein Serine-Threonine Kinases/metabolism , Structure-Activity RelationshipABSTRACT
[reaction: see text] A novel ring opening ring closing metathesis (ROM-RCM) was demonstrated for cyclic conjugated dienes, effecting the excision of a C(2)H(2) unit and a net ring contraction. Applying the ring contraction metathesis, new 14-membered ring macrolide antibiotics were synthesized in a single step from existing 16-membered ring macrolides. This new class of macrolide antibiotics will provide access to new therapeutics for the treatment of macrolide-resistant bacterial infections.
