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

Autor: 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.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2017 Mar 15; Vol. 27 (6), pp. 1364-1370. Date of Electronic Publication: 2017 Feb 09.
DOI: 10.1016/j.bmcl.2017.02.012
Abstrakt: 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 OX 2 R subtype and culminating in the discovery of 23, a highly potent, OX 2 R-selective molecule that exhibited a promising in vivo profile. Further structural modification led to an unexpected restoration of OX 1 R antagonism. Herein, these changes are discussed and a rationale for selectivity based on computational modeling is proposed.
(Copyright © 2017 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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