Lead optimization of a pyrazolo[1,5-a]pyrimidin-7(4H)-one scaffold to identify potent, selective and orally bioavailable KDM5 inhibitors suitable for in vivo biological studies

Bioorg Med Chem Lett. 2016 Aug 15;26(16):4036-41. doi: 10.1016/j.bmcl.2016.06.078. Epub 2016 Jun 29.

Abstract

Starting with a lead [1,5-a]pyrimidin-7(4H)-one-containing molecule (1), we generated potent, selective and orally bioavailable KDM5 inhibitors. Using structure- and property-based approaches, we designed 48 with improved cell potency (PC9 H3K4Me3 EC50=0.34μM). Furthermore, 48 maintained suitable physiochemical properties and displayed an excellent pharmacokinetic (PK) profile in mice. When dosed orally in mice at 50mg/kg twice a day (BID), 48 showed an unbound maximal plasma concentration (Cmax) >15-fold over its cell EC50, thereby providing a robust chemical probe for studying KDM5 biological functions in vivo.

Keywords: Drug resistance; Epigenetics; Histone demethylase; KDM5; Lead optimization; Selective KDM5 inhibitors.

MeSH terms

  • Administration, Oral
  • Animals
  • Binding Sites
  • Crystallography, X-Ray
  • Female
  • Half-Life
  • Histones / metabolism
  • Humans
  • Liver / metabolism
  • Mice
  • Microsomes, Liver / metabolism
  • Molecular Dynamics Simulation
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry*
  • Pyrazoles / pharmacokinetics
  • Pyrimidinones / blood
  • Pyrimidinones / chemical synthesis
  • Pyrimidinones / chemistry*
  • Pyrimidinones / pharmacokinetics
  • Rats
  • Retinoblastoma-Binding Protein 2 / antagonists & inhibitors*
  • Retinoblastoma-Binding Protein 2 / metabolism
  • Structure-Activity Relationship

Substances

  • Histones
  • Pyrazoles
  • Pyrimidinones
  • pyrazolo(1,5-a)pyrimidin-7(4H)-one
  • KDM5A protein, mouse
  • Retinoblastoma-Binding Protein 2