2. Academic Validation
  3. Discovery of dual orexin receptor antagonists with rat sleep efficacy enabled by expansion of the acetonitrile-assisted/diphosgene-mediated 2,4-dichloropyrimidine synthesis

Discovery of dual orexin receptor antagonists with rat sleep efficacy enabled by expansion of the acetonitrile-assisted/diphosgene-mediated 2,4-dichloropyrimidine synthesis

  • Bioorg Med Chem Lett. 2014 May 1;24(9):2079-85. doi: 10.1016/j.bmcl.2014.03.052.
Anthony J Roecker 1,  Swati P Mercer 2,  C Meacham Harrell 3,  Susan L Garson 3,  Steven V Fox 3,  Anthony L Gotter 3,  Thomayant Prueksaritanont 4,  Tamara D Cabalu 4,  Donghui Cui 4,  Wei Lemaire 5,  Christopher J Winrow 3,  John J Renger 3,  Paul J Coleman 2
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, United States. Electronic address: anthony_roecker@merck.com.
  • 2 Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, United States.
  • 3 Department of Neuroscience, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, United States.
  • 4 Department of Drug Metabolism, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, United States.
  • 5 Department of In Vitro Pharmacology, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, United States.
PMID: 24704030 DOI: 10.1016/j.bmcl.2014.03.052
Abstract

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.

Keywords

Antagonist; Bioactivation; Orexin; Pyrimidine; Sleep.

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