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Proline bis-amides as potent dual orexin receptor antagonists |
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| 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 |
| Institution: | Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. |
| 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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