title: Design and Synthesis of Selurampanel, a Novel Orally Active and Competitive AMPA Receptor Antagonist.
abstract: 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-1H-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.
authors.affiliation: Global Discovery Chemistry, Novartis Institute for Biomedical Research, 4002, Basel, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Orain
authors.affiliation: Global Discovery Chemistry, Novartis Institute for Biomedical Research, 4002, Basel, Switzerland.
authors.forename: Engin
authors.initials: E
authors.lastname: Tasdelen
authors.affiliation: Global Discovery Chemistry, Novartis Institute for Biomedical Research, 4002, Basel, Switzerland.
authors.forename: Samuel
authors.initials: S
authors.lastname: Haessig
authors.affiliation: Global Discovery Chemistry, Novartis Institute for Biomedical Research, 4002, Basel, Switzerland.
authors.forename: Manuel
authors.initials: M
authors.lastname: Koller
authors.affiliation: Global Discovery Chemistry, Novartis Institute for Biomedical Research, 4002, Basel, Switzerland.
authors.forename: Anne
authors.initials: A
authors.lastname: Picard
authors.affiliation: Global Discovery Chemistry, Novartis Institute for Biomedical Research, 4002, Basel, Switzerland.
authors.forename: Celine
authors.initials: C
authors.lastname: Dubois
authors.affiliation: Previously: Neuroscience Disease Area, Novartis Institute for Biomedical Research, 4002, Basel, Switzerland.
authors.forename: Kurt
authors.initials: K
authors.lastname: Lingenhoehl
authors.affiliation: Metabolism and Pharmacokinetics, Novartis Institute for Biomedical Research, 4002, Basel, Switzerland.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Desrayaud
authors.affiliation: Global Discovery Chemistry, Novartis Institute for Biomedical Research, 4002, Basel, Switzerland.
authors.forename: Phillip
authors.initials: P
authors.lastname: Floersheim
authors.affiliation: Global Discovery Chemistry, Novartis Institute for Biomedical Research, 4002, Basel, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Carcache
authors.affiliation: Previously: Neuroscience Disease Area, Novartis Institute for Biomedical Research, 4002, Basel, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Urwyler
authors.affiliation: Center for Proteomic Chemistry, Novartis Institute for Biomedical Research, 4002, Basel, Switzerland.
authors.forename: Joerg
authors.initials: J
authors.lastname: Kallen
authors.affiliation: Global Discovery Chemistry, Novartis Institute for Biomedical Research, 4002, Basel, Switzerland.
authors.forename: Henri
authors.identifier: 0000-0003-4831-6488
authors.initials: H
authors.lastname: Mattes
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D015195:Drug Design; D004597:Electroshock; D051379:Mice; D056004:Molecular Dynamics Simulation; D017434:Protein Structure, Tertiary; D052999:Quinazolinones / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012640:Seizures / Q000188:drug therapy; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism
chemical_list: D052999:Quinazolinones; D018091:Receptors, AMPA; D013449:Sulfonamides; C000591013:selurampanel
keywords: AMPA; antagonists; epilepsy; glutamate; quinazolinediones; selurampanel