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: 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 10 Pg. 4291-308 (May 28 2015) ISSN: 1520-4804 [Electronic] United States
• PMID: 25905800 (Publication Type: Journal Article)

Chemical References

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

Topics

• 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, pharmacology)
• Thiophenes (chemistry, pharmacology)
• Young Adult