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

Scott D Kuduk; Jason W Skudlarek; Christina N DiMarco; Joseph G Bruno; Mark H Pausch; Julie A O'Brien; Tamara D Cabalu; Joanne Stevens; Joseph Brunner; Pamela L Tannenbaum; Susan L Garson; Alan T Savitz; Charles M Harrell; Anthony L Gotter; Christopher J Winrow; John J Renger; Paul J Coleman

doi:10.1016/j.bmcl.2015.04.066

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. Epub 2015 Apr 29.

Authors

Scott D Kuduk¹, Jason W Skudlarek², Christina N DiMarco², Joseph G Bruno³, Mark H Pausch³, Julie A O'Brien³, Tamara D Cabalu⁴, Joanne Stevens³, Joseph Brunner³, Pamela L Tannenbaum³, Susan L Garson⁵, Alan T Savitz⁵, Charles M Harrell⁵, Anthony L Gotter⁵, Christopher J Winrow⁵, John J Renger⁵, Paul J Coleman²

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.

MeSH terms

Animals
Dogs
Half-Life
Mice
Orexin Receptor Antagonists / chemistry*
Orexin Receptor Antagonists / pharmacokinetics
Orexin Receptor Antagonists / therapeutic use
Orexin Receptors / chemistry*
Orexin Receptors / metabolism
Piperidines / chemistry*
Piperidines / pharmacokinetics
Piperidines / therapeutic use
Protein Binding
Pyrimidines / chemistry
Rats
Sleep Initiation and Maintenance Disorders / drug therapy
Sleep Initiation and Maintenance Disorders / veterinary
Structure-Activity Relationship
Triazoles / chemistry*
Triazoles / pharmacokinetics
Triazoles / therapeutic use

Substances

MK-6096
MK-8133
Orexin Receptor Antagonists
Orexin Receptors
Piperidines
Pyrimidines
Triazoles