Discovery of dual orexin receptor antagonists with rat sleep efficacy enabled by expansion of the acetonitrile-assisted/diphosgene-mediated 2,4-dichloropyrimidine synthesis.
Recent clinical studies have demonstrated that dual orexin receptor antagonists (OX1R and OX2R antagonists or DORAs) represent a novel treatment option for insomnia patients. Previously we have disclosed several compounds in the diazepane amide DORA series with excellent potency and both preclinical and clinical sleep efficacy. Additional SAR studies in this series were enabled by the expansion of the acetonitrile-assisted, diphosgene-mediated 2,4-dichloropyrimidine synthesis to novel substrates providing an array of Western heterocycles. These heterocycles were utilized to synthesize analogs in short order with high levels of potency on orexin 1 and orexin 2 receptors as well as in vivo sleep efficacy in the rat.
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, United States. Electronic address: anthony_roecker@merck.com.
Anthony J
AJ
Roecker
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, United States.
Swati P
SP
Mercer
Department of Neuroscience, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, United States.
C Meacham
CM
Harrell
Department of Neuroscience, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, United States.
Susan L
SL
Garson
Department of Neuroscience, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, United States.
Steven V
SV
Fox
Department of Neuroscience, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, United States.
Anthony L
AL
Gotter
Department of Drug Metabolism, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, United States.
Thomayant
T
Prueksaritanont
Department of Drug Metabolism, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, United States.
Tamara D
TD
Cabalu
Department of Drug Metabolism, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, United States.
Donghui
D
Cui
Department of In Vitro Pharmacology, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, United States.
Wei
W
Lemaire
Department of Neuroscience, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, United States.
Christopher J
CJ
Winrow
Department of Neuroscience, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, United States.
John J
JJ
Renger
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, United States.
Paul J
PJ
Coleman
D000818:Animals; D055808:Drug Discovery; D006801:Humans; D000068796:Orexin Receptor Antagonists; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D012890:Sleep / Q000187:drug effects*; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy
D000068796:Orexin Receptor Antagonists; D011743:Pyrimidines; C513879:2,4-dichloropyrimidine
Antagonist; Bioactivation; Orexin; Pyrimidine; Sleep