2. Academic Validation
  3. Identification of MK-8133: An orexin-2 selective receptor antagonist with favorable development properties

Identification of MK-8133: An orexin-2 selective receptor antagonist with favorable development properties

  • Bioorg Med Chem Lett. 2015 Jun 15;25(12):2488-92. doi: 10.1016/j.bmcl.2015.04.066.
Scott D Kuduk 1,  Jason W Skudlarek 2,  Christina N DiMarco 2,  Joseph G Bruno 3,  Mark H Pausch 3,  Julie A O'Brien 3,  Tamara D Cabalu 4,  Joanne Stevens 3,  Joseph Brunner 3,  Pamela L Tannenbaum 3,  Susan L Garson 5,  Alan T Savitz 5,  Charles M Harrell 5,  Anthony L Gotter 5,  Christopher J Winrow 5,  John J Renger 5,  Paul J Coleman 2
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. Electronic address: skuduk@noviratherapeutics.com.
  • 2 Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
  • 3 Department of Pharmacology, Merck Research Laboratories, West Point, PA 19486, USA.
  • 4 Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, USA.
  • 5 Department of Neuroscience, Merck Research Laboratories, West Point, PA 19486, USA.
PMID: 25981685 DOI: 10.1016/j.bmcl.2015.04.066
Abstract

Antagonism of orexin receptors has shown clinical efficacy as a novel paradigm for the treatment of insomnia and related disorders. Herein, molecules related to the dual orexin receptor antagonist filorexant were transformed into compounds that were selective for the OX2R subtype. Judicious selection of the substituents on the pyridine ring and benzamide groups led to 6b; which was highly potent, OX2R selective, and exhibited excellent development properties.

Keywords

Antagonist; GPCR; Insomnia; Orexin; Sleep.

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