Q1 · MEDICINE
Article
Author: Hurst, Raymond S. ; Chen, Laigao ; Liu, JianHua ; Lotarski, Susan M. ; Zasadny, Kenneth R. ; Patel, Nandini C. ; Karki, Kapil ; O’Donnell, Christopher J. ; Seymour, Patricia A. ; Hoffmann, William E. ; Scialis, Renato J. ; Osgood, Sarah M. ; Weber, Mark L. ; Chang, Cheng ; Lazzaro, John T. ; Schwarz, Jacob ; Obach, R. Scott ; McGinnis, Dina F. ; Pandit, Jayvardhan ; Wei, Yunjing ; Bryce, Dianne K. ; Schmidt, Christopher J. ; Hou, Xinjun J. ; Hajós, Mihály ; Shaffer, Christopher L. ; Xie, Longfei
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.