Discovery of 2,5-diarylnicotinamides as selective orexin-2 receptor antagonists (2-SORAs).
The orexin (or hypocretin) system has been identified as a novel target for the treatment of insomnia due to the wealth of biological and genetic data discovered over the past decade. Recently, clinical proof-of-concept was achieved for the treatment of primary insomnia using dual (OX1R/OX2R) orexin receptor antagonists. However, elucidation of the pharmacology associated with selective orexin-2 receptor antagonists (2-SORAs) has been hampered by the lack of orally bioavailable, highly selective small molecule probes. Herein, the discovery and optimization of a novel series of 2,5-diarylnicotinamides as potent and orally bioavailable orexin-2 receptor selective antagonists is described. A compound from this series demonstrated potent sleep promotion when dosed orally to EEG telemetrized rats.
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. Electronic address: swati_mercer@merck.com.
Swati P
SP
Mercer
Anthony J
AJ
Roecker
Susan
S
Garson
Duane R
DR
Reiss
C
C
Meacham Harrell
Kathy L
KL
Murphy
Joseph G
JG
Bruno
Rodney A
RA
Bednar
Wei
W
Lemaire
Donghui
D
Cui
Tamara D
TD
Cabalu
Cuyue
C
Tang
Thomayant
T
Prueksaritanont
George D
GD
Hartman
Steven D
SD
Young
Christopher J
CJ
Winrow
John J
JJ
Renger
Paul J
PJ
Coleman
D000818:Animals; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D006801:Humans; D009539:Nicotinic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D013329:Structure-Activity Relationship
D009539:Nicotinic Acids; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; C038997:nicotinanilide
Hypocretin; Insomnia; Orexin receptor antagonists; Rat sleep EEG; Selective orexin-2 receptor antagonists