2. Academic Validation
  3. 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)

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.
Christopher L Shaffer,  Nandini C Patel,  Jacob Schwarz,  Renato J Scialis,  Yunjing Wei,  Xinjun J Hou,  Longfei Xie,  Kapil Karki,  Dianne K Bryce,  Sarah M Osgood,  William E Hoffmann,  John T Lazzaro,  Cheng Chang,  Dina F McGinnis,  Susan M Lotarski,  JianHua Liu,  R Scott Obach,  Mark L Weber,  Laigao Chen,  Kenneth R Zasadny,  Patricia A Seymour,  Christopher J Schmidt,  Mihály Hajós,  Raymond S Hurst,  Jayvardhan Pandit,  Christopher J O'Donnell
PMID: 25905800 DOI: 10.1021/acs.jmedchem.5b00300
Abstract

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.

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