Abstract
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•PF-8380 has been used as a template to design a new series of ATX inhibitors.•Reduction of crystallinity was key to improving solubility of the new series.•Selectivity and good oral exposure was achieved with this series.•Compound 12 shows a direct PK-PD relationship with inhibition of production of LPA.
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 benzoxazolone 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 experiments.