title: 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.
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.
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK. simon.e.ward@gsk.com
authors.forename: Simon E
authors.initials: SE
authors.lastname: Ward
authors.forename: Mark
authors.initials: M
authors.lastname: Harries
authors.forename: Laura
authors.initials: L
authors.lastname: Aldegheri
authors.forename: Daniele
authors.initials: D
authors.lastname: Andreotti
authors.forename: Stuart
authors.initials: S
authors.lastname: Ballantine
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Bax
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Harris
authors.forename: Andy J
authors.initials: AJ
authors.lastname: Harker
authors.forename: Jesper
authors.initials: J
authors.lastname: Lund
authors.forename: Rosemary
authors.initials: R
authors.lastname: Melarange
authors.forename: Anna
authors.initials: A
authors.lastname: Mingardi
authors.forename: Claudette
authors.initials: C
authors.lastname: Mookherjee
authors.forename: Julie
authors.initials: J
authors.lastname: Mosley
authors.forename: Marta
authors.initials: M
authors.lastname: Neve
authors.forename: Beatrice
authors.initials: B
authors.lastname: Oliosi
authors.forename: Roberto
authors.initials: R
authors.lastname: Profeta
authors.forename: Kathrine J
authors.initials: KJ
authors.lastname: Smith
authors.forename: Paul W
authors.initials: PW
authors.lastname: Smith
authors.forename: Simone
authors.initials: S
authors.lastname: Spada
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Thewlis
authors.forename: Shahnaz P
authors.initials: SP
authors.lastname: Yusaf
mesh_terms: D000284:Administration, Oral; D000494:Allosteric Regulation; D000818:Animals; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism; D002144:Callithrix; D002460:Cell Line; D018360:Crystallography, X-Ray; D004285:Dogs; D006801:Humans; D007192:Indenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000502:physiology*; D013045:Species Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D001798:Blood Proteins; D007192:Indenes; C551959:N-(5-(6-fluoro-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl)-2-propanesulfonamide; D011725:Pyridines; D018091:Receptors, AMPA; D013449:Sulfonamides