N-Glycine-sulfonamides as potent dual orexin 1/orexin 2 receptor antagonists.
A series of dual OX(1)R/OX(2)R orexin antagonists was prepared based on a N-glycine-sulfonamide core. SAR studies of a screening hit led to compounds with low nanomolar affinity for both receptors and good oral bioavailability. One of these compounds, 47, has demonstrated in vivo activity in rats following oral administration.
Aissaoui
Hamed
H
Drug Discovery Chemistry and Biochemistry, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Basel-Land, Switzerland. aissaoui.hamed@actelion.com
Koberstein
Ralf
R
Zumbrunn
Cornelia
C
Gatfield
John
J
Brisbare-Roch
Catherine
C
Jenck
Francois
F
Treiber
Alexander
A
Boss
Christoph
C
D000818:Animals; D001682:Biological Availability; D001812:Blood-Brain Barrier; D005998:Glycine / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D064446:Orexin Receptors; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D013449:Sulfonamides; D005998:Glycine