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Discovery of MK-3697: a selective orexin 2 receptor antagonist (2-SORA) for the treatment of insomnia.
Roecker, Anthony J; Reger, Thomas S; Mattern, M Christa; Mercer, Swati P; Bergman, Jeffrey M; Schreier, John D; Cube, Rowena V; Cox, Christopher D; Li, Dansu; Lemaire, Wei; Bruno, Joseph G; Harrell, C Meacham; Garson, Susan L; Gotter, Anthony L; Fox, Steven V; Stevens, Joanne; Tannenbaum, Pamela L; Prueksaritanont, Thomayant; Cabalu, Tamara D; Cui, Donghui; Stellabott, Joyce; Hartman, George D; Young, Steven D; Winrow, Christopher J; Renger, John J; Coleman, Paul J.
Affiliation
  • Roecker AJ; 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.
  • Reger TS; Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States. Electronic address: treger@gtweed.com.
  • Mattern MC; Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
  • Mercer SP; Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
  • Bergman JM; Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
  • Schreier JD; Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
  • Cube RV; Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
  • Cox CD; Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
  • Li D; Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
  • Lemaire W; Department of In Vitro Pharmacology, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
  • Bruno JG; Department of In Vitro Pharmacology, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
  • Harrell CM; Department of Neuroscience, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
  • Garson SL; Department of Neuroscience, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
  • Gotter AL; Department of Neuroscience, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
  • Fox SV; Department of In Vivo Pharmacology, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
  • Stevens J; Department of In Vivo Pharmacology, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
  • Tannenbaum PL; Department of In Vivo Pharmacology, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
  • Prueksaritanont T; Department of Drug Metabolism, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
  • Cabalu TD; Department of Drug Metabolism, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
  • Cui D; Department of Drug Metabolism, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
  • Stellabott J; Department of Basic Pharmaceutical Sciences, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
  • Hartman GD; Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
  • Young SD; Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
  • Winrow CJ; Department of Neuroscience, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
  • Renger JJ; Department of Neuroscience, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
  • Coleman PJ; Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, United States.
Bioorg Med Chem Lett ; 24(20): 4884-90, 2014 Oct 15.
Article in En | MEDLINE | ID: mdl-25248679
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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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pyridines / Thiazoles / Drug Discovery / Orexin Receptor Antagonists / Sleep Initiation and Maintenance Disorders Limits: Animals / Humans Language: En Journal: Bioorg Med Chem Lett Journal subject: BIOQUIMICA / QUIMICA Year: 2014 Document type: Article
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pyridines / Thiazoles / Drug Discovery / Orexin Receptor Antagonists / Sleep Initiation and Maintenance Disorders Limits: Animals / Humans Language: En Journal: Bioorg Med Chem Lett Journal subject: BIOQUIMICA / QUIMICA Year: 2014 Document type: Article