In Vitro and In Silico Characterization of Lemborexant (E2006), a Novel Dual Orexin Receptor Antagonist

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 362; no. 2; pp. 287 - 295
• Main Authors: Beuckmann, Carsten Theodor, Suzuki, Michiyuki, Ueno, Takashi, Nagaoka, Kazuya, Arai, Tohru, Higashiyama, Hiroyuki
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2017
• Subjects: Animals; Binding Sites; CHO Cells; Computer Simulation; Cricetinae; Cricetulus; HEK293 Cells; Humans; Mice; Orexin Receptor Antagonists - chemistry; Orexin Receptor Antagonists - metabolism; Orexin Receptors - chemistry; Orexin Receptors - metabolism; Protein Structure, Secondary; Rats; OXR; CHO; kon; hOX1R; MT1R; PLAP; OX1R; PDB; RBA; HEK293; mOX2R; koff; MD; DORA; mOXB; hOXB; MT2R; E2006; OX2R; hOX2R; 2-SORA; MM-GBSA; OXB; EMPA; OXA; REM; Bmax; FDSS; Ki
• ISSN: 0022-3565; 1521-0103; 1521-0103
• DOI: 10.1124/jpet.117.241422

Orexin (hypocretin) neuropeptides have, among others, been implicated in arousal/sleep control, and antagonizing the orexin signaling pathway has been previously demonstrated to promote sleep in animals and humans. This mechanism opens up a new therapeutic approach to curb excessive wakefulness in insomnia disorder rather than to promote sleep-related signaling. Here we describe the preclinical pharmacological in vitro and in silico characterization of lemborexant ((1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide)), a dual orexin receptor antagonist (DORA), as a novel experimental therapeutic agent for the symptomatic treatment of insomnia disorder and compare its properties to two other DORAs, almorexant and suvorexant. Lemborexant binds to both orexin receptors and functionally inhibits them in a competitive manner with low nanomolar potency, without any species difference apparent among human, rat, and mouse receptors. Binding and dissociation kinetics on both orexin receptors are rapid. Lemborexant is selective for both orexin receptors over 88 other receptors, transporters, and ion channels of important physiologic function. In silico modeling of lemborexant into the orexin receptors showed that it assumes the same type of conformation within the receptor-binding pocket as suvorexant, the π-stacked horseshoe-like conformation.