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.

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.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Administration, Oral
  • Allosteric Regulation
  • Animals
  • Biological Availability
  • Blood Proteins / metabolism
  • Blood-Brain Barrier / metabolism
  • Callithrix
  • Cell Line
  • Crystallography, X-Ray
  • Dogs
  • Humans
  • Indenes / chemical synthesis*
  • Indenes / pharmacokinetics
  • Indenes / pharmacology
  • Macaca fascicularis
  • Male
  • Microsomes, Liver / metabolism
  • Models, Molecular
  • Protein Binding
  • Protein Structure, Tertiary
  • Pyridines / chemical synthesis*
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / physiology*
  • Species Specificity
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / pharmacokinetics
  • Sulfonamides / pharmacology

Substances

  • Blood Proteins
  • Indenes
  • N-(5-(6-fluoro-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl)-2-propanesulfonamide
  • Pyridines
  • Receptors, AMPA
  • Sulfonamides

Associated data

  • PDB/2XHD