1,3-Biarylureas as selective non-peptide antagonists of the orexin-1 receptor.
This communication reports SARs for the first orexin-1 receptor antagonist series of 1-aryl-3-quinolin-4-yl and 1-aryl-3-naphthyridin-4-yl ureas. One of these compounds, 31 (SB-334867), has excellent selectivity for the orexin-1 receptor, blood-brain barrier permeability and shows in vivo activity following ip dosing.
Porter
R A
RA
GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park North, Third Avenue, Harlow, CM19 5AW, Essex, UK. porter@sbphrd.com
Chan
W N
WN
Coulton
S
S
Johns
A
A
Hadley
M S
MS
Widdowson
K
K
Jerman
J C
JC
Brough
S J
SJ
Coldwell
M
M
Smart
D
D
Jewitt
F
F
Jeffrey
P
P
Austin
N
N
D000818:Animals; D001583:Benzoxazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D001812:Blood-Brain Barrier; D016466:CHO Cells; D002490:Central Nervous System / Q000378:metabolism; D006224:Cricetinae; D006801:Humans; D007211:Indoles / Q000737:chemistry; D007262:Infusions, Intravenous; D009287:Naphthyridines / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D064446:Orexin Receptors; D010539:Permeability; D011804:Quinolines / Q000737:chemistry; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*
C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; D007211:Indoles; D009287:Naphthyridines; D064446:Orexin Receptors; D011804:Quinolines; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; C030374:indole; D014508:Urea; C037219:quinoline