The discovery and characterization of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor potentiator N-{(3S,4S)-4-[4-(5-cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide (PF-04958242)

J Med Chem. 2015 May 28;58(10):4291-308. doi: 10.1021/acs.jmedchem.5b00300. Epub 2015 May 14.


A unique tetrahydrofuran ether class of highly potent α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiators has been identified using rational and structure-based drug design. An acyclic lead compound, containing an ether-linked isopropylsulfonamide and biphenyl group, was pharmacologically augmented by converting it to a conformationally constrained tetrahydrofuran to improve key interactions with the human GluA2 ligand-binding domain. Subsequent replacement of the distal phenyl motif with 2-cyanothiophene to enhance its potency, selectivity, and metabolic stability afforded N-{(3S,4S)-4-[4-(5-cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide (PF-04958242, 3), whose preclinical characterization suggests an adequate therapeutic index, aided by low projected human oral pharmacokinetic variability, for clinical studies exploring its ability to attenuate cognitive deficits in patients with schizophrenia.

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Aged
  • Animals
  • Binding Sites
  • Disease Models, Animal
  • Dogs
  • Dose-Response Relationship, Drug
  • Drug Discovery
  • Drug Evaluation, Preclinical / methods*
  • Drug Stability
  • Female
  • Humans
  • Male
  • Memory, Short-Term / drug effects
  • Mice, Inbred C57BL
  • Middle Aged
  • Protein Conformation
  • Rats, Sprague-Dawley
  • Receptors, AMPA / metabolism*
  • Schizophrenia / drug therapy
  • Structure-Activity Relationship
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*
  • Thiophenes / chemistry
  • Thiophenes / pharmacology*
  • Young Adult


  • PF-04958242
  • Receptors, AMPA
  • Sulfonamides
  • Thiophenes