Discovery of polar spirocyclic orally bioavailable urea inhibitors of soluble epoxide hydrolase

Bioorg Chem. 2018 Oct;80:655-667. doi: 10.1016/j.bioorg.2018.07.014. Epub 2018 Jul 17.

Abstract

Spirocyclic 1-oxa-9-azaspiro[5.5]undecan-4-amine scaffold was explored as a basis for the design of potential inhibitors of soluble epoxide hydrolase (sEH). Synthesis and testing of the initial SAR-probing library followed by biochemical testing against sEH allowed nominating a racemic lead compound (±)-22. The latter showed remarkable (> 0.5 mM) solubility in aqueous phosphate buffer solution, unusually low (for sEH inhibitors) lipophilicity as confirmed by experimentally determined logD7.4 of 0.99, and an excellent oral bioavailability in mice (as well as other pharmacokinetic characteristics). Individual enantiomer profiling revealed that the inhibitory potency primarily resided with the dextrorotatory eutomer (+)-22 (IC50 4.99 ± 0.18 nM). For the latter, a crystal structure of its complex with a C-terminal domain of sEH was obtained and resolved. These data fully validate (+)-22 as a new non-racemic advanced lead compound for further development as a potential therapeutic agent for use in such areas as cardiovascular disease, inflammation and pain.

Keywords: 1-Oxa-9-azaspiro[5.5]undecan-4-amine; Distomer; Eutomer; Low LogD; Oral bioavailability; Orthogonal periphery group variation; Phosphate buffer solubility; Prins reaction; Protein-ligand crystal structure; Spirocyclic.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Epoxide Hydrolases / antagonists & inhibitors*
  • Epoxide Hydrolases / metabolism
  • Humans
  • Inhibitory Concentration 50
  • Molecular Docking Simulation
  • Recombinant Proteins / metabolism
  • Solubility
  • Spiro Compounds / chemistry*
  • Spiro Compounds / pharmacology*
  • Urea / analogs & derivatives*
  • Urea / pharmacology*

Substances

  • Enzyme Inhibitors
  • Recombinant Proteins
  • Spiro Compounds
  • Urea
  • Epoxide Hydrolases