The exploration of aza-quinolines as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors with low brain exposure

Bioorg Med Chem. 2020 Dec 1;28(23):115791. doi: 10.1016/j.bmc.2020.115791. Epub 2020 Oct 3.


GlaxoSmithKline and Astex Pharmaceuticals recently disclosed the discovery of the potent H-PGDS inhibitor GSK2894631A 1a (IC50 = 9.9 nM) as part of a fragment-based drug discovery collaboration with Astex Pharmaceuticals. This molecule exhibited good murine pharmacokinetics, allowing it to be utilized to explore H-PGDS pharmacology in vivo. Yet, with prolonged dosing at higher concentrations, 1a induced CNS toxicity. Looking to attenuate brain penetration in this series, aza-quinolines, were prepared with the intent of increasing polar surface area. Nitrogen substitutions at the 6- and 8-positions of the quinoline were discovered to be tolerated by the enzyme. Subsequent structure activity studies in these aza-quinoline scaffolds led to the identification of 1,8-naphthyridine 1y (IC50 = 9.4 nM) as a potent peripherally restricted H-PGDS inhibitor. Compound 1y is efficacious in four in vivo inflammatory models and exhibits no CNS toxicity.

Keywords: CNS exposure; H-PGDS; H-PGDS inhibitor; Hematopoietic prostaglandin D synthase; PGD(2); Prostaglandin D(2).

MeSH terms

  • Animals
  • Aza Compounds / chemistry*
  • Binding Sites
  • Brain / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Crystallography, X-Ray
  • Drug Stability
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Intramolecular Oxidoreductases / antagonists & inhibitors
  • Intramolecular Oxidoreductases / metabolism
  • Kinetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Dynamics Simulation
  • Muscle, Skeletal / chemistry
  • Muscle, Skeletal / metabolism
  • Quinolines / chemistry*
  • Rats
  • Structure-Activity Relationship


  • Aza Compounds
  • Enzyme Inhibitors
  • Quinolines
  • Intramolecular Oxidoreductases
  • HPGDS protein, human