Author/Authors :
Jeffrey M. Bergman، نويسنده , , Anthony J. Roecker، نويسنده , , Swati P. Mercer، نويسنده , , Rodney A. Bednar، نويسنده , , Duane R. Reiss، نويسنده , , Richard W. Ransom، نويسنده , , C. Meacham Harrell، نويسنده , , Douglas J. Pettibone، نويسنده , , Wei Lemaire، نويسنده , , Kathy L. Murphy، نويسنده , , Chunze Li، نويسنده , , Thomayant Prueksaritanont، نويسنده , , Christopher J. Winrow، نويسنده , , John J. Renger، نويسنده , , Kenneth S. Koblan، نويسنده , , George D. Hartman، نويسنده , , Paul J. Coleman، نويسنده ,
Abstract :
A series of OX2R/OX1R 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.
Keywords :
Brain penetrant , Orexin , insomnia , Narcolepsy , Dual orexin antagonist , Benzimidazole , Orexin inhibitor , Proline bis-amide , Potent
