Discovery of (1R,2S)‑2-{[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)‑N‑(5-fluoropyridin-2-yl)cyclopropanecarboxamide (E2006): A Potent and Efficacious Oral Orexin Receptor Antagonist

The orexin/hypocretin receptors are a family of G protein-coupled receptors and consist of orexin-1 (OX1) and orexin-2 (OX2) receptor subtypes. Orexin receptors are expressed throughout the central nervous system and are involved in the regulation of the sleep/wake cycle. Because modulation of these...

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Veröffentlicht in:Journal of medicinal chemistry 2015-06, Vol.58 (11), p.4648-4664
Hauptverfasser: Yoshida, Yu, Naoe, Yoshimitsu, Terauchi, Taro, Ozaki, Fumihiro, Doko, Takashi, Takemura, Ayumi, Tanaka, Toshiaki, Sorimachi, Keiichi, Beuckmann, Carsten T, Suzuki, Michiyuki, Ueno, Takashi, Ozaki, Shunsuke, Yonaga, Masahiro
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container_end_page 4664
container_issue 11
container_start_page 4648
container_title Journal of medicinal chemistry
container_volume 58
creator Yoshida, Yu
Naoe, Yoshimitsu
Terauchi, Taro
Ozaki, Fumihiro
Doko, Takashi
Takemura, Ayumi
Tanaka, Toshiaki
Sorimachi, Keiichi
Beuckmann, Carsten T
Suzuki, Michiyuki
Ueno, Takashi
Ozaki, Shunsuke
Yonaga, Masahiro
description The orexin/hypocretin receptors are a family of G protein-coupled receptors and consist of orexin-1 (OX1) and orexin-2 (OX2) receptor subtypes. Orexin receptors are expressed throughout the central nervous system and are involved in the regulation of the sleep/wake cycle. Because modulation of these receptors constitutes a promising target for novel treatments of disorders associated with the control of sleep and wakefulness, such as insomnia, the development of orexin receptor antagonists has emerged as an important focus in drug discovery research. Here, we report the design, synthesis, characterization, and structure–activity relationships (SARs) of novel orexin receptor antagonists. Various modifications made to the core structure of a previously developed compound (-)-5, the lead molecule, resulted in compounds with improved chemical and pharmacological profiles. The investigation afforded a potential therapeutic agent, (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)­oxy]­methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)­cyclopropanecarboxamide (E2006), an orally active, potent orexin antagonist. The efficacy was demonstrated in mice in an in vivo study by using sleep parameter measurements.
doi_str_mv 10.1021/acs.jmedchem.5b00217
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subjects Administration, Oral
Amides - chemistry
Aminopyridines - administration & dosage
Aminopyridines - pharmacology
Animals
Calcium - metabolism
Cells, Cultured
Cyclopropanes - chemistry
Drug Design
Drug Discovery
Humans
Male
Mice
Mice, Inbred C57BL
Microsomes, Liver - drug effects
Microsomes, Liver - metabolism
Models, Molecular
Molecular Structure
Orexin Receptor Antagonists
Orexin Receptors - metabolism
Pyrimidines - administration & dosage
Pyrimidines - pharmacology
Structure-Activity Relationship
title Discovery of (1R,2S)‑2-{[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)‑N‑(5-fluoropyridin-2-yl)cyclopropanecarboxamide (E2006): A Potent and Efficacious Oral Orexin Receptor Antagonist
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