2. Academic Validation
  3. Design and Synthesis of Selurampanel, a Novel Orally Active and Competitive AMPA Receptor Antagonist

Design and Synthesis of Selurampanel, a Novel Orally Active and Competitive AMPA Receptor Antagonist

  • ChemMedChem. 2017 Feb 3;12(3):197-201. doi: 10.1002/cmdc.201600467.
David Orain 1,  Engin Tasdelen 1,  Samuel Haessig 1,  Manuel Koller 1,  Anne Picard 1,  Celine Dubois 1,  Kurt Lingenhoehl 2,  Sandrine Desrayaud 3,  Phillip Floersheim 1,  David Carcache 1,  Stephan Urwyler 2,  Joerg Kallen 4,  Henri Mattes 1
Affiliations

Affiliations

  • 1 Global Discovery Chemistry, Novartis Institute for Biomedical Research, 4002, Basel, Switzerland.
  • 2 Previously: Neuroscience Disease Area, Novartis Institute for Biomedical Research, 4002, Basel, Switzerland.
  • 3 Metabolism and Pharmacokinetics, Novartis Institute for Biomedical Research, 4002, Basel, Switzerland.
  • 4 Center for Proteomic Chemistry, Novartis Institute for Biomedical Research, 4002, Basel, Switzerland.
PMID: 27863026 DOI: 10.1002/cmdc.201600467
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.

Keywords

AMPA; antagonists; epilepsy; glutamate; quinazolinediones; selurampanel.

Figures
Products