Novel pyrazolo-tetrahydropyridines as potent orexin receptor antagonists.
A novel series of dual orexin receptor antagonists was prepared by heteroaromatic five-membered ring system replacement of the dimethoxyphenyl moiety contained in the tetrahydroisoquinoline core skeleton of almorexant. Thus, replacement of the dimethoxyphenyl by a substituted pyrazole and additional optimization of the substitution pattern of the phenethyl motif allowed the identification of potent antagonists with low nanomolar affinity for hOX(1)R and hOX(2)R. The synthesis and structure-activity relationship of these novel antagonists will be discussed in this communication. These investigations furnished several suitable candidates for further evaluation in in vivo studies in rats.
Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland. thierry.sifferlen@actelion.com
Thierry
T
Sifferlen
Christoph
C
Boss
Emmanuelle
E
Cottreel
Ralf
R
Koberstein
Markus
M
Gude
Hamed
H
Aissaoui
Thomas
T
Weller
John
J
Gatfield
Catherine
C
Brisbare-Roch
Francois
F
Jenck
D000081:Acetamides / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology; D064446:Orexin Receptors; D011720:Pyrazoles / Q000737:chemistry*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000081:Acetamides; D007546:Isoquinolines; D064446:Orexin Receptors; D011720:Pyrazoles; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; C031280:pyrazole; C519150:almorexant