Proline bis-amides as potent dual orexin receptor antagonists

A series of potent dual orexin antagonists was prepared based on a proline bis-amide core that demonstrate in vivo central activity in a pharmacodyamic model of orexin activity. A series of OX 2R/OX 1R dual orexin antagonists was prepared based on a proline bis-amide identified as a screening lead....

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Published in:Bioorganic & medicinal chemistry 2008-02, Vol.18 (4), p.1425-1430
Main Authors: Bergman, Jeffrey M., Roecker, Anthony J., Mercer, Swati P., Bednar, Rodney A., Reiss, Duane R., Ransom, Richard W., Meacham Harrell, C., Pettibone, Douglas J., Lemaire, Wei, Murphy, Kathy L., Li, Chunze, Prueksaritanont, Thomayant, Winrow, Christopher J., Renger, John J., Koblan, Kenneth S., Hartman, George D., Coleman, Paul J.
Format: Article
Language:English
Subjects:
Amides - chemical synthesis
Amides - pharmacology
Animals
Benzimidazole
Benzimidazoles - chemistry
Benzimidazoles - pharmacology
Biological and medical sciences
Brain penetrant
Dual orexin antagonist
Insomnia
Intracellular Signaling Peptides and Proteins - chemistry
Intracellular Signaling Peptides and Proteins - pharmacology
Kinetics
Medical sciences
Narcolepsy
Neuropeptides - chemistry
Neuropeptides - pharmacology
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Orexin
Orexin inhibitor
Orexin Receptors
Orexins
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Pharmacology. Drug treatments
Potent
Proline - analogs & derivatives
Proline - chemical synthesis
Proline - pharmacology
Proline bis-amide
Rats
Receptors, G-Protein-Coupled - antagonists & inhibitors
Receptors, Neuropeptide - antagonists & inhibitors
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Summary:A series of potent dual orexin antagonists was prepared based on a proline bis-amide core that demonstrate in vivo central activity in a pharmacodyamic model of orexin activity. A series of OX 2R/OX 1R dual orexin antagonists was prepared based on a proline bis-amide identified as a screening lead. Through a combination of classical and library synthesis, potency enhancing replacements for both amide portions were discovered. N-methylation of the benzimidazole moiety within the lead structure significantly reduced P-gp susceptibility while increasing potency, giving rise to good brain penetration. A compound from this series has demonstrated in vivo central activity when dosed peripherally in a pharmacodynamic model of orexin activity.
ISSN:0960-894X
0968-0896
1464-3405
1464-3391
DOI:10.1016/j.bmcl.2008.01.001