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
  • 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.
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