Discovery of MK-3697: A selective orexin 2 receptor antagonist (2-SORA) for the treatment of insomnia |
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| Affiliation: | 1. Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States;2. Department of In Vitro Pharmacology, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States;3. Department of Neuroscience, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States;4. Department of In Vivo Pharmacology, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States;5. Department of Drug Metabolism, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States;6. Department of Basic Pharmaceutical Sciences, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States;1. Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA;2. Department of Molecular Structure, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA;3. Department of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA;4. Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA;5. Department of HTS and Molecular Pharmacology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA;6. Comparative Biology and Safety Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA;7. Department of Medicinal Chemistry, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA;8. Department of Molecular Structure, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA;1. Orthobond Corporation, 675 U.S. 1, North Brunswick, NJ 08902, USA;2. St Jude Children’s Research Hospital, Department of Chemical Biology, 262 Danny Thomas Place, Memphis, TN 38105, USA;3. Jacobs Engineering, 155 N, 400 W., Suite 550, Salt Lake City, UT 84103, USA;4. Arup Laboratories, 500 Chipeta Way, Salt Lake City, UT 84108, USA;5. Genysis Labs, 391 Orange St, Salt Lake City, UT 84104, USA;6. Sera Prognostics, 2749 East Parleys Way, Suite 200, Salt Lake City, UT 84109, USA;7. MediProPharma, 419 Wakara Way, #207B, Salt Lake City, UT 84108, USA;8. Core Diagnostics, 2458 Embarcadero Way, Palo Alto, CA 94303, USA;9. Navigen, 383 Colorow Dr, Salt Lake City, UT 84108, USA;10. VioGen Biosciences, 1290 West, 2320 South, Suite E, Salt Lake City, UT 84119, USA;11. Karyopharm Therapeutics, 85 Wells Ave., 2nd Floor, Newton, MA 02459, USA;12. Myriad Genetic Laboratories, 320 Wakara Way, Salt Lake City, UT 84108, USA;13. New Hope Baptist Church, 149 Highland Ave., East Lansing, MI 48823, USA;14. AvidXchange, 6415 South, 3000 East, Suite 150, Salt Lake City, UT 84121, USA;1. Department of Discovery Chemistry Merck & Co., Inc., West Point, PA 19486, USA;2. Department of Pharmacology Merck & Co., Inc., West Point, PA 19486, USA;3. Department of Neuroscience Merck & Co., Inc., West Point, PA 19486, USA;4. Department of Drug Metabolism Merck & Co., Inc., West Point, PA 19486, USA;5. Department of Chemistry Modeling & Informatics Merck & Co., Inc., West Point, PA 19486, USA;6. Department of Analytical Chemistry Merck & Co., Inc., West Point, PA 19486, USA;7. WuXi AppTec Co., Ltd, Shanghai, China |
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| 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. |
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| Keywords: | Orexin receptors Insomnia 2-SORA Antagonists Neurotransmitters |
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