| Institution: | 1. Department of Medicinal Chemistry, MRL, Merck & Co., Inc., West Point, PA 19486, USA;2. Department of Chemical Capabilities & Screening, MRL, Merck & Co., Inc., West Point, PA 19486, USA;3. Department of In Vitro Pharmacology, MRL, Merck & Co., Inc., West Point, PA 19486, USA;4. Department of Drug Metabolism, MRL, Merck & Co., Inc., West Point, PA 19486, USA;5. Department of In Vivo Pharmacology, MRL, Merck & Co., Inc., West Point, PA 19486, USA;6. Department of Neuroscience, MRL, Merck & Co., Inc., West Point, PA 19486, USA;7. Discovery Pharmaceutical Sciences, MRL, Merck & Co., Inc., West Point, PA 19486, USA |
| 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. |
