title: 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).
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.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Shaffer
authors.forename: Nandini C
authors.initials: NC
authors.lastname: Patel
authors.forename: Jacob
authors.initials: J
authors.lastname: Schwarz
authors.forename: Renato J
authors.initials: RJ
authors.lastname: Scialis
authors.forename: Yunjing
authors.initials: Y
authors.lastname: Wei
authors.forename: Xinjun J
authors.initials: XJ
authors.lastname: Hou
authors.forename: Longfei
authors.initials: L
authors.lastname: Xie
authors.forename: Kapil
authors.initials: K
authors.lastname: Karki
authors.forename: Dianne K
authors.initials: DK
authors.lastname: Bryce
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Osgood
authors.forename: William E
authors.initials: WE
authors.lastname: Hoffmann
authors.forename: John T
authors.initials: JT
authors.lastname: Lazzaro
authors.forename: Cheng
authors.initials: C
authors.lastname: Chang
authors.forename: Dina F
authors.initials: DF
authors.lastname: McGinnis
authors.forename: Susan M
authors.initials: SM
authors.lastname: Lotarski
authors.forename: JianHua
authors.initials: J
authors.lastname: Liu
authors.forename: R Scott
authors.initials: RS
authors.lastname: Obach
authors.forename: Mark L
authors.initials: ML
authors.lastname: Weber
authors.forename: Laigao
authors.initials: L
authors.lastname: Chen
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Zasadny
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Seymour
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schmidt
authors.forename: Mihály
authors.initials: M
authors.lastname: Hajós
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Hurst
authors.forename: Jayvardhan
authors.initials: J
authors.lastname: Pandit
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001665:Binding Sites; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004355:Drug Stability; D005260:Female; D006801:Humans; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D011487:Protein Conformation; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*; D055815:Young Adult
chemical_list: C000600968:PF-04958242; D018091:Receptors, AMPA; D013449:Sulfonamides; D013876:Thiophenes