Design and synthesis of conformationally constrained N,N-disubstituted 1,4-diazepanes as potent orexin receptor antagonists.
Orexins are neuropeptides that regulate wakefulness and arousal. Small molecule antagonists of orexin receptors may provide a novel therapy for the treatment of insomnia and other sleep disorders. In this Letter we describe the design and synthesis of conformationally constrained N,N-disubstituted 1,4-diazepanes as orexin receptor antagonists. The design of these constrained analogs was guided by an understanding of the preferred solution and solid state conformation of the diazepane central ring.
Coleman
Paul J
PJ
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, USA. paul_coleman@merck.com
Schreier
John D
JD
McGaughey
Georgia B
GB
Bogusky
Michael J
MJ
Cox
Christopher D
CD
Hartman
George D
GD
Ball
Richard G
RG
Harrell
C Meacham
CM
Reiss
Duane R
DR
Prueksaritanont
Thomayant
T
Winrow
Christopher J
CJ
Renger
John J
JJ
D000818:Animals; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004285:Dogs; D006801:Humans; D008958:Models, Molecular; D064446:Orexin Receptors; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D012893:Sleep Wake Disorders / Q000188:drug therapy
C545228:1,4-diazepane; D001381:Azepines; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide