Development of autotaxin inhibitors: A series of zinc binding triazoles

Bioorg Med Chem Lett. 2018 Jul 15;28(13):2279-2284. doi: 10.1016/j.bmcl.2018.05.030. Epub 2018 May 21.

Abstract

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.

Keywords: Autotaxin inhibition; Idiopathic pulmonary fibrosis; PK/PD; Solubility; hERG inhibition.

MeSH terms

  • Administration, Oral
  • Animals
  • Benzoxazoles / pharmacology
  • Drug Design*
  • Drug Stability
  • Humans
  • Male
  • Microsomes / metabolism
  • Phosphodiesterase Inhibitors / administration & dosage
  • Phosphodiesterase Inhibitors / chemical synthesis
  • Phosphodiesterase Inhibitors / pharmacokinetics
  • Phosphodiesterase Inhibitors / pharmacology*
  • Phosphoric Diester Hydrolases / metabolism*
  • Piperazines / pharmacology
  • Rats, Sprague-Dawley
  • Solubility
  • Triazoles / administration & dosage
  • Triazoles / chemical synthesis
  • Triazoles / pharmacokinetics
  • Triazoles / pharmacology*

Substances

  • 6-(3-(piperazin-1-yl)propanoyl)benzo(d)oxazol-2(3H)-one
  • Benzoxazoles
  • Phosphodiesterase Inhibitors
  • Piperazines
  • Triazoles
  • Phosphoric Diester Hydrolases
  • alkylglycerophosphoethanolamine phosphodiesterase