title: Discovery of Highly Potent Dual Orexin Receptor Antagonists via a Scaffold-Hopping Approach.
abstract: Starting from suvorexant (trade name Belsomra), we successfully identified interesting templates leading to potent dual orexin receptor antagonists (DORAs) via a scaffold-hopping approach. Structure-activity relationship optimization allowed us not only to improve the antagonistic potency on both orexin 1 and orexin 2 receptors (Ox1 and Ox2, respectively), but also to increase metabolic stability in human liver microsomes (HLM), decrease time-dependent inhibition of cytochrome P450 (CYP) 3A4, and decrease P-glycoprotein (Pgp)-mediated efflux. Compound 80 c [{(1S,6R)-3-(6,7-difluoroquinoxalin-2-yl)-3,8-diazabicyclo[4.2.0]octan-8-yl}(4-methyl-[1,1'-biphenyl]-2-yl)methanone] is a potent and selective DORA that inhibits the stimulating effects of orexin peptides OXA and OXB at both Ox1 and Ox2. In calcium-release assays, 80 c was found to exhibit an insurmountable antagonistic profile at both Ox1 and Ox2, while displaying a sleep-promoting effect in rat and dog models, similar to that of the benchmark compound suvorexant.
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, 4123, Allschwil, Switzerland. heidmab@actelion.com.
authors.forename: Bibia
authors.initials: B
authors.lastname: Heidmann
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, 4123, Allschwil, Switzerland.
authors.forename: John
authors.initials: J
authors.lastname: Gatfield
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, 4123, Allschwil, Switzerland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Roch
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, 4123, Allschwil, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Treiber
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, 4123, Allschwil, Switzerland.
authors.forename: Simone
authors.initials: S
authors.lastname: Tortoioli
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, 4123, Allschwil, Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: Brotschi
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, 4123, Allschwil, Switzerland.
authors.forename: Jodi T
authors.initials: JT
authors.lastname: Williams
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, 4123, Allschwil, Switzerland.
authors.forename: Martin H
authors.initials: MH
authors.lastname: Bolli
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, 4123, Allschwil, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Abele
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, 4123, Allschwil, Switzerland.
authors.forename: Thierry
authors.initials: T
authors.lastname: Sifferlen
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, 4123, Allschwil, Switzerland.
authors.forename: François
authors.initials: F
authors.lastname: Jenck
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, 4123, Allschwil, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Boss
mesh_terms: D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D000068796:Orexin Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D064446:Orexin Receptors / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012890:Sleep / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D051544:Cytochrome P-450 CYP3A
keywords: drug design; orexin receptor antagonists; scaffold hopping; sleep disorders; structure-activity relationships