New quinoline NK3 receptor antagonists with CNS activity.
Lead optimisation starting from the previously reported selective quinoline NK(3) receptor antagonists talnetant 2 (SB-223412) and 3 (SB-222200) led to the identification of 3-aminoquinoline NK(3) antagonist 10 (GSK172981) with excellent CNS penetration. Investigation of a structurally related series of sulfonamides with reduced lipophilicity led to the discovery of 20 (GSK256471). Both 10 and 20 are high affinity, potent NK(3) receptor antagonists which despite having different degrees of CNS penetration produced excellent NK(3) receptor occupancy in an ex vivo binding study in gerbil cortex.
Smith
Paul W
PW
Medicinal Chemistry, Neuroscience CEDD GlaxoSmithKline Research & Development, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. Paul.W.Smith@GSK.com
Wyman
Paul A
PA
Lovell
Peter
P
Goodacre
Caroline
C
Serafinowska
Halina T
HT
Vong
Antonio
A
Harrington
Frank
F
Flynn
Sean
S
Bradley
Daniel M
DM
Porter
Rod
R
Coggon
Sara
S
Murkitt
Graham
G
Searle
Kirsten
K
Thomas
David R
DR
Watson
Jeannette M
JM
Martin
William
W
Wu
Zining
Z
Dawson
Lee A
LA
D000588:Amines / Q000378:metabolism; D000818:Animals; D019540:Area Under Curve; D001921:Brain / Q000378:metabolism; D002490:Central Nervous System / Q000187:drug effects*; D002540:Cerebral Cortex / Q000196:embryology; D005849:Gerbillinae; D008297:Male; D008956:Models, Chemical; D011804:Quinolines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors*
D000588:Amines; C539893:GSK256471; D011804:Quinolines; D018042:Receptors, Neurokinin-3; C109112:SB 222200; C106716:SB 223412