ABSTRACT
Reports of a high-affinity ligand for E-selectin, sialyl di-Lewis(x) (sLe(x)Le(x), 1), motivated us to incorporate modifications to previously reported biphenyl-based inhibitors that would provide additional interactions with the protein. These compounds were assayed for the ability to inhibit the binding of sialyl Lewis(x) (sLe(x), 2) bearing HL-60 cells to E-, P-, and L-selectin fusion proteins. We report that dimeric or trimeric compounds containing multiple components of simple nonoligosaccharide selectin antagonists inhibit sLe(x)-dependent binding with significantly enhanced potency over the monomeric compound. The enhanced potency is consistent with additional binding interactions within a single selectin lectin domain; however, multivalent interaction with multiple lectin domains as a possible alternative cannot be ruled out. Compound 15e (TBC1269) showed optimal in vitro activity from this class of antagonists and is currently under development for use in the treatment of asthma.
Subject(s)
Anti-Asthmatic Agents/chemical synthesis , Biphenyl Compounds/chemical synthesis , Cell Adhesion/drug effects , Mannosides/chemical synthesis , Selectins/metabolism , Anti-Asthmatic Agents/chemistry , Anti-Asthmatic Agents/pharmacology , Asthma/drug therapy , Biphenyl Compounds/pharmacology , HL-60 Cells/drug effects , HL-60 Cells/metabolism , Humans , Mannose/analogs & derivatives , Mannosides/pharmacology , Models, MolecularABSTRACT
Nitrophenylcarbamates were reacted with various amines to yield ureas. A high throughput purification of these crude products was achieved by using polymer bound scavengers.