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Investigation of orexin-2 selective receptor antagonists: Structural modifications resulting in dual orexin receptor antagonists.
Skudlarek, Jason W; DiMarco, Christina N; Babaoglu, Kerim; Roecker, Anthony J; Bruno, Joseph G; Pausch, Mark A; O'Brien, Julie A; Cabalu, Tamara D; Stevens, Joanne; Brunner, Joseph; Tannenbaum, Pamela L; Wuelfing, W Peter; Garson, Susan L; Fox, Steven V; Savitz, Alan T; Harrell, Charles M; Gotter, Anthony L; Winrow, Christopher J; Renger, John J; Kuduk, Scott D; Coleman, Paul J.
Afiliación
  • Skudlarek JW; Department of Medicinal Chemistry, MRL, Merck & Co., Inc., West Point, PA 19486, USA. Electronic address: jason_skudlarek@merck.com.
  • DiMarco CN; Department of Medicinal Chemistry, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
  • Babaoglu K; Department of Chemical Capabilities & Screening, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
  • Roecker AJ; Department of Medicinal Chemistry, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
  • Bruno JG; Department of In Vitro Pharmacology, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
  • Pausch MA; Department of In Vitro Pharmacology, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
  • O'Brien JA; Department of In Vitro Pharmacology, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
  • Cabalu TD; Department of Drug Metabolism, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
  • Stevens J; Department of In Vivo Pharmacology, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
  • Brunner J; Department of Neuroscience, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
  • Tannenbaum PL; Department of In Vivo Pharmacology, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
  • Wuelfing WP; Discovery Pharmaceutical Sciences, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
  • Garson SL; Department of Neuroscience, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
  • Fox SV; Department of In Vivo Pharmacology, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
  • Savitz AT; Department of In Vivo Pharmacology, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
  • Harrell CM; Department of Neuroscience, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
  • Gotter AL; Department of Neuroscience, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
  • Winrow CJ; Department of Neuroscience, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
  • Renger JJ; Department of Neuroscience, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
  • Kuduk SD; Novira Therapeutics, Inc., a part of Janssen Pharmaceuticals, Doylestown, PA 18902, USA(1).
  • Coleman PJ; Department of Medicinal Chemistry, MRL, Merck & Co., Inc., West Point, PA 19486, USA.
Bioorg Med Chem Lett ; 27(6): 1364-1370, 2017 03 15.
Article en En | MEDLINE | ID: mdl-28216403
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.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Orexinas / Antagonistas de los Receptores de Orexina Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2017 Tipo del documento: Article
Texto completo
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XML
PubMed Links
Buscar en Google

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Orexinas / Antagonistas de los Receptores de Orexina Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2017 Tipo del documento: Article