Discovery of a series of 2-phenyl-N-(2-(pyrrolidin-1-yl)phenyl)acetamides as novel molecular switches that modulate modes of K(v)7.2 (KCNQ2) channel pharmacology: identification of (S)-2-phenyl-N-(2-(pyrrolidin-1-yl)phenyl)butanamide (ML252) as a potent, brain penetrant K(v)7.2 channel inhibitor

J Med Chem. 2012 Aug 9;55(15):6975-9. doi: 10.1021/jm300700v. Epub 2012 Jul 26.

Abstract

A potent and selective inhibitor of KCNQ2, (S)-5 (ML252, IC(50) = 69 nM), was discovered after a high-throughput screen of the MLPCN library was performed. SAR studies revealed a small structural change (ethyl group to hydrogen) caused a functional shift from antagonist to agonist activity (37, EC(50) = 170 nM), suggesting an interaction at a critical site for controlling gating of KCNQ2 channels.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Brain / metabolism*
  • Databases, Factual
  • High-Throughput Screening Assays
  • Humans
  • KCNQ2 Potassium Channel / antagonists & inhibitors*
  • KCNQ2 Potassium Channel / chemistry
  • Microsomes, Liver / metabolism
  • Permeability
  • Phenylbutyrates / chemical synthesis*
  • Phenylbutyrates / chemistry
  • Phenylbutyrates / pharmacokinetics
  • Potassium Channel Blockers / chemical synthesis*
  • Potassium Channel Blockers / chemistry
  • Potassium Channel Blockers / pharmacokinetics
  • Pyrrolidines / chemical synthesis*
  • Pyrrolidines / chemistry
  • Pyrrolidines / pharmacokinetics
  • Rats
  • Small Molecule Libraries
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • 2-phenyl-N-(2-(pyrrolidin-1-yl)phenyl)butanamide
  • KCNQ2 Potassium Channel
  • Phenylbutyrates
  • Potassium Channel Blockers
  • Pyrrolidines
  • Small Molecule Libraries