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.
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.
Ward
Simon E
SE
Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK. simon.e.ward@gsk.com
Harries
Mark
M
Aldegheri
Laura
L
Andreotti
Daniele
D
Ballantine
Stuart
S
Bax
Benjamin D
BD
Harris
Andrew J
AJ
Harker
Andy J
AJ
Lund
Jesper
J
Melarange
Rosemary
R
Mingardi
Anna
A
Mookherjee
Claudette
C
Mosley
Julie
J
Neve
Marta
M
Oliosi
Beatrice
B
Profeta
Roberto
R
Smith
Kathrine J
KJ
Smith
Paul W
PW
Spada
Simone
S
Thewlis
Kevin M
KM
Yusaf
Shahnaz P
SP
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
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