Discovery of substituted lactams as novel dual orexin receptor antagonists. Synthesis, preliminary structure-activity relationship studies and efforts towards improved metabolic stability and pharmacokinetic properties. Part 1.
Starting from a thiazolidin-4-one HTS hit, a novel series of substituted lactams was identified and developed as dual orexin receptor antagonists. In this Letter, we describe our initial efforts towards the improvement of potency and metabolic stability. These investigations delivered optimized lead compounds with CNS drug-like properties suitable for further optimization.
Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
Thierry
T
Sifferlen
Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
Amandine
A
Boller
Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
Audrey
A
Chardonneau
Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
Emmanuelle
E
Cottreel
Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
Johannes
J
Hoecker
Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
Hamed
H
Aissaoui
Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
Jodi T
JT
Williams
Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
Christine
C
Brotschi
Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
Bibia
B
Heidmann
Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
Romain
R
Siegrist
Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
John
J
Gatfield
Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
Alexander
A
Treiber
Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
Catherine
C
Brisbare-Roch
Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
Francois
F
Jenck
Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland. Electronic address: christoph.boss@actelion.com.
Christoph
C
Boss
D000818:Animals; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D007769:Lactams / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015394:Molecular Structure; D000068796:Orexin Receptor Antagonists; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D007769:Lactams; D000068796:Orexin Receptor Antagonists
CNS drug discovery; G-protein coupled receptors; Metabolic stability; Orexin antagonists; Structure–activity relationship studies