2. Academic Validation
  3. Proline bis-amides as potent dual orexin receptor antagonists

Proline bis-amides as potent dual orexin receptor antagonists

  • Bioorg Med Chem Lett. 2008 Feb 15;18(4):1425-30. doi: 10.1016/j.bmcl.2008.01.001.
Jeffrey M Bergman 1,  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
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
PMID: 18207395 DOI: 10.1016/j.bmcl.2008.01.001
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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