Proline bis-amides as potent dual orexin receptor antagonists.
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.
Bergman
Jeffrey M
JM
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
Roecker
Anthony J
AJ
Mercer
Swati P
SP
Bednar
Rodney A
RA
Reiss
Duane R
DR
Ransom
Richard W
RW
Meacham Harrell
C
C
Pettibone
Douglas J
DJ
Lemaire
Wei
W
Murphy
Kathy L
KL
Li
Chunze
C
Prueksaritanont
Thomayant
T
Winrow
Christopher J
CJ
Renger
John J
JJ
Koblan
Kenneth S
KS
Hartman
George D
GD
Coleman
Paul J
PJ
D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D009479:Neuropeptides / Q000737:chemistry / Q000494:pharmacology; D064446:Orexin Receptors; D000068797:Orexins; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*
D000577:Amides; D001562:Benzimidazoles; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D011392:Proline