Discovery of N-[(2S)-5-(6-fluoro-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide, a novel clinical AMPA receptor positive modulator

  • J Med Chem. 2010 Aug 12;53(15):5801-12. doi: 10.1021/jm1005429.
Simon E Ward  1 ,  Mark Harries ,  Laura Aldegheri ,  Daniele Andreotti ,  Stuart Ballantine ,  Benjamin D Bax ,  Andrew J Harris ,  Andy J Harker ,  Jesper Lund ,  Rosemary Melarange ,  Anna Mingardi ,  Claudette Mookherjee ,  Julie Mosley ,  Marta Neve ,  Beatrice Oliosi ,  Roberto Profeta ,  Kathrine J Smith ,  Paul W Smith ,  Simone Spada ,  Kevin M Thewlis ,  Shahnaz P Yusaf
Affiliations
  • 1. Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK. [email protected]
PMID: 20614889 DOI: 10.1021/jm1005429
Abstract

A series of AMPA Receptor positive allosteric modulators has been optimized from poorly penetrant leads to identify molecules with excellent preclinical pharmacokinetics and CNS penetration. These discoveries led to 17i, a potent, efficacious CNS penetrant molecule with an excellent pharmacokinetic profile across preclinical species, which is well tolerated and is also orally bioavailable in humans.