Conformational analysis of N,N-disubstituted-1,4-diazepane orexin receptor antagonists and implications for receptor binding |
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| Authors: | Christopher D. Cox Georgia B. McGaughey Michael J. Bogusky David B. Whitman Richard G. Ball Christopher J. Winrow John J. Renger Paul J. Coleman |
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| Affiliation: | 1. Department of Medicinal Chemistry, Merck Research Laboratories, WP14-2, PO Box 4, Sumneytown Pike, West Point, PA 19486, USA;2. Department of Pharmaceutical Research, Merck Research Laboratories, PO Box 2000, 126 E. Lincoln Highway, Rahway, NJ 07065, USA;3. Department of Depression and Circadian Disorders, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, USA |
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| Abstract: | NMR spectroscopy, X-ray crystallography, and molecular modeling studies indicate that N,N-disubstituted-1,4-diazepane orexin receptor antagonists exist in an unexpected low-energy conformation that is characterized by an intramolecular π-stacking interaction and a twist-boat ring conformation. Synthesis and evaluation of a macrocycle that enforces a similar conformation suggest that this geometry mimics the bioactive conformation. |
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