Discovery of dual orexin receptor antagonists (DORAs) for the treatment of insomnia.
Orexins are excitatory neuropeptides that have a critical role in maintaining wakefulness. Orexin receptor antagonists promote sleep in animals and humans. Indeed, small molecule orexin receptor antagonists have demonstrated clinical proof-of-concept in the treatment of primary insomnia. This review describes optimization of orexin receptor antagonists across diverse structural classes with a focus on how molecules were designed to optimize potency, physicochemical properties, pharmacokinetics, brain penetration, and in vivo activity.
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, USA. paul_coleman@merck.com
Paul J
PJ
Coleman
Christopher D
CD
Cox
Anthony J
AJ
Roecker
D000818:Animals; D055808:Drug Discovery; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy* / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
D007211:Indoles; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D013141:Spiro Compounds; D044005:Tetrahydroisoquinolines