Development of Autotaxin Inhibitors Part 1: A Series of Zinc Binding Triazoles

A series of inhibitors of Autotaxin (ATX) has been developed using the binding mode of known inhibitor, PF 8380, as a template. Replacement of the benzoxazolinone with a triazole zinc-binding motif reduced crystallinity and improved solubility relative to PF-8380. Modification of the linker region removed hERG activity and led to compound 12 - a selective, high affinity, orally-bioavailable inhibitor of ATX. Compound 12 concentration dependently inhibits autotaxin and formation of LPA in vivo, as shown in pharmacokinetic-pharmacodynamic experiment