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  • Title: Proline bis-amides as potent dual orexin receptor antagonists.
    Author: Bergman JM, Roecker AJ, Mercer SP, Bednar RA, Reiss DR, Ransom RW, Meacham Harrell C, Pettibone DJ, Lemaire W, Murphy KL, Li C, Prueksaritanont T, Winrow CJ, Renger JJ, Koblan KS, Hartman GD, Coleman PJ.
    Journal: Bioorg Med Chem Lett; 2008 Feb 15; 18(4):1425-30. PubMed ID: 18207395.
    Abstract:
    A series of OX(2)R/OX(1)R 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.
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