Proline bis-amides as potent dual orexin receptor antagonists.

Proline bis-amides as potent dual orexin receptor antagonists.

Bioorganic & medicinal chemistry letters (2008-01-22)

Jeffrey M Bergman, Anthony J Roecker, Swati P Mercer, Rodney A Bednar, Duane R Reiss, Richard W Ransom, C Meacham Harrell, Douglas J Pettibone, Wei Lemaire, Kathy L Murphy, Chunze Li, Thomayant Prueksaritanont, Christopher J Winrow, John J Renger, Kenneth S Koblan, George D Hartman, Paul J Coleman

PMID18207395

摘要

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.