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.
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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)
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Chemical References |
- PF-04958242
- Receptors, AMPA
- Sulfonamides
- Thiophenes
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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
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