Discovery of MK-3697: a selective orexin 2 receptor antagonist (2-SORA) for the treatment of insomnia

Bioorg Med Chem Lett. 2014 Oct 15;24(20):4884-90. doi: 10.1016/j.bmcl.2014.08.041.

Anthony J Roecker ¹, Thomas S Reger ², M Christa Mattern ³, Swati P Mercer ³, Jeffrey M Bergman ³, John D Schreier ³, Rowena V Cube ³, Christopher D Cox ³, Dansu Li ³, Wei Lemaire ⁴, Joseph G Bruno ⁴, C Meacham Harrell ⁵, Susan L Garson ⁵, Anthony L Gotter ⁵, Steven V Fox ⁶, Joanne Stevens ⁶, Pamela L Tannenbaum ⁶, Thomayant Prueksaritanont ⁷, Tamara D Cabalu ⁷, Donghui Cui ⁷, Joyce Stellabott ⁸, George D Hartman ³, Steven D Young ³, Christopher J Winrow ⁵, John J Renger ⁵, Paul J Coleman ³

Affiliations

1 Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, 770 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, 770 Sumneytown Pike, West Point, PA 19486, United States. Electronic address: treger@gtweed.com.
3 Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
4 Department of In Vitro Pharmacology, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
5 Department of Neuroscience, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
6 Department of In Vivo Pharmacology, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
7 Department of Drug Metabolism, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
8 Department of Basic Pharmaceutical Sciences, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.

PMID: 25248679 DOI: 10.1016/j.bmcl.2014.08.041

Abstract

Orexin receptor antagonists have demonstrated clinical utility for the treatment of insomnia. The majority of clinical efforts to date have focused on the development of dual orexin receptor antagonists (DORAs), small molecules that antagonize both the orexin 1 and orexin 2 receptors. Our group has recently disclosed medicinal chemistry efforts to identify highly potent, orally bioavailable selective orexin 2 receptor antagonists (2-SORAs) that possess acceptable profiles for clinical development. Herein we report additional SAR studies within the 'triaryl' amide 2-SORA series focused on improvements in compound stability in acidic media and time-dependent inhibition of CYP3A4. These studies resulted in the discovery of 2,5-disubstituted isonicotinamide 2-SORAs such as compound 24 that demonstrated improved stability and TDI profiles as well as excellent sleep efficacy across species.

Keywords

2-SORA; Antagonists; Insomnia; Neurotransmitters; Orexin receptors.

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