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

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.

• Authors: Anthony J Roecker, Swati P Mercer, C Meacham Harrell, Susan L Garson, Steven V Fox, Anthony L Gotter, Thomayant Prueksaritanont, Tamara D Cabalu, Donghui Cui, Wei Lemaire, Christopher J Winrow, John J Renger, Paul J Coleman
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 24 Issue 9 Pg. 2079-85 (May 01 2014) ISSN: 1464-3405 [Electronic] England
• PMID: 24704030 (Publication Type: Journal Article)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Orexin Receptor Antagonists
• Pyrimidines
• 2,4-dichloropyrimidine

Topics

• Animals
• Drug Discovery
• Humans
• Orexin Receptor Antagonists
• Pyrimidines (chemical synthesis, chemistry, pharmacology)
• Rats
• Sleep (drug effects)
• Sleep Initiation and Maintenance Disorders (drug therapy)