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.
Drug Discovery Chemistry and Biochemistry, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Basel-Land, Switzerland. aissaoui.hamed@actelion.com
Hamed
H
Aissaoui
Ralf
R
Koberstein
Cornelia
C
Zumbrunn
John
J
Gatfield
Catherine
C
Brisbare-Roch
Francois
F
Jenck
Alexander
A
Treiber
Christoph
C
Boss
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