Conformational analysis of N,N-disubstituted-1,4-diazepane orexin receptor antagonists and implications for receptor binding

Christopher D Cox; Georgia B McGaughey; Michael J Bogusky; David B Whitman; Richard G Ball; Christopher J Winrow; John J Renger; Paul J Coleman

doi:10.1016/j.bmcl.2009.04.026

Conformational analysis of N,N-disubstituted-1,4-diazepane orexin receptor antagonists and implications for receptor binding

Bioorg Med Chem Lett. 2009 Jun 1;19(11):2997-3001. doi: 10.1016/j.bmcl.2009.04.026. Epub 2009 Apr 14.

Authors

Christopher D Cox¹, Georgia B McGaughey, Michael J Bogusky, David B Whitman, Richard G Ball, Christopher J Winrow, John J Renger, Paul J Coleman

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. [email protected]

PMID: 19406641
DOI: 10.1016/j.bmcl.2009.04.026

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 pi-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.

MeSH terms

Crystallography, X-Ray
Heterocyclic Compounds, 1-Ring / chemical synthesis
Heterocyclic Compounds, 1-Ring / chemistry*
Macrocyclic Compounds / chemical synthesis
Macrocyclic Compounds / chemistry
Magnetic Resonance Spectroscopy
Models, Chemical
Orexin Receptors
Protein Binding
Receptors, G-Protein-Coupled / antagonists & inhibitors*
Receptors, G-Protein-Coupled / metabolism
Receptors, Neuropeptide / antagonists & inhibitors*
Receptors, Neuropeptide / metabolism

Substances

Heterocyclic Compounds, 1-Ring
Macrocyclic Compounds
Orexin Receptors
Receptors, G-Protein-Coupled
Receptors, Neuropeptide