Investigation of orexin-2 selective receptor antagonists: Structural modifications resulting in dual orexin receptor antagonists

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

doi:10.1016/j.bmcl.2017.02.012

Investigation of orexin-2 selective receptor antagonists: Structural modifications resulting in dual orexin receptor antagonists

Bioorg Med Chem Lett. 2017 Mar 15;27(6):1364-1370. doi: 10.1016/j.bmcl.2017.02.012. Epub 2017 Feb 9.

Authors

Jason W Skudlarek¹, Christina N DiMarco², Kerim Babaoglu³, Anthony J Roecker², Joseph G Bruno⁴, Mark A Pausch⁴, Julie A O'Brien⁴, Tamara D Cabalu⁵, Joanne Stevens⁶, Joseph Brunner⁷, Pamela L Tannenbaum⁶, W Peter Wuelfing⁸, Susan L Garson⁷, Steven V Fox⁶, Alan T Savitz⁶, Charles M Harrell⁷, Anthony L Gotter⁷, Christopher J Winrow⁷, John J Renger⁷, Scott D Kuduk⁹, Paul J Coleman²

Affiliations

¹ Department of Medicinal Chemistry, MRL, Merck & Co., Inc., West Point, PA 19486, USA. Electronic address: jason_skudlarek@merck.com.
² Department of Medicinal Chemistry, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
³ Department of Chemical Capabilities & Screening, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
⁴ Department of In Vitro Pharmacology, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
⁵ Department of Drug Metabolism, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
⁶ Department of In Vivo Pharmacology, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
⁷ Department of Neuroscience, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
⁸ Discovery Pharmaceutical Sciences, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
⁹ Novira Therapeutics, Inc., a part of Janssen Pharmaceuticals, Doylestown, PA 18902, USA(1).

PMID: 28216403
DOI: 10.1016/j.bmcl.2017.02.012

Abstract

In an ongoing effort to explore the use of orexin receptor antagonists for the treatment of insomnia, dual orexin receptor antagonists (DORAs) were structurally modified, resulting in compounds selective for the OX₂R subtype and culminating in the discovery of 23, a highly potent, OX₂R-selective molecule that exhibited a promising in vivo profile. Further structural modification led to an unexpected restoration of OX₁R antagonism. Herein, these changes are discussed and a rationale for selectivity based on computational modeling is proposed.

Keywords: Antagonist; GPCR; Insomnia; Orexin; Sleep.

MeSH terms

Animals
Electroencephalography
Electromyography
Molecular Structure
Orexin Receptor Antagonists / chemistry
Orexin Receptor Antagonists / pharmacology*
Orexins / antagonists & inhibitors*
Rats

Substances

Orexin Receptor Antagonists
Orexins