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Design and Synthesis of Selurampanel, a Novel Orally Active and Competitive AMPA Receptor Antagonist
Author(s) -
Orain David,
Tasdelen Engin,
Haessig Samuel,
Koller Manuel,
Picard Anne,
Dubois Celine,
Lingenhoehl Kurt,
Desrayaud Sandrine,
Floersheim Phillip,
Carcache David,
Urwyler Stephan,
Kallen Joerg,
Mattes Henri
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600467
Subject(s) - ampa receptor , isoxazole , antagonist , isopropyl , chemistry , in vivo , pharmacology , potency , stereochemistry , competitive antagonist , sulfonamide , receptor , in vitro , medicine , biochemistry , biology , nmda receptor , medicinal chemistry , microbiology and biotechnology
A series of potent quinazolinedione sulfonamide antagonists of the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionic acid (AMPA) receptor were designed and synthesized. The structure–activity relationships (SAR) and in vivo activity of the series were investigated. In particular, compound 1 S (selurampanel; N ‐[7‐isopropyl‐6‐(2‐methylpyrazol‐3‐yl)‐2,4‐dioxo‐1 H ‐quinazolin‐3‐yl]methanesulfonamide) has shown excellent oral potency against maximal electroshock seizure (MES)‐induced generalized tonic–clonic seizures in rodents as well as significant activity in patients suffering from various forms of epilepsy. The X‐ray crystal structure of selurampanel bound to the AMPA receptor hGluA was also obtained.