Design, synthesis, and structure–activity relationships of a series of novel N-aryl-2-phenylcyclopropanecarboxamide that are potent and orally active orexin receptor antagonists

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

“…Non-REM sleep-promoting effect in this sleep experiment was thought to be saturated at 10 and 30 mg/kg dose by taking of the PK results into consideration (Table 6). These data suggested that the compound 34 possessed robust sleeppromoting effects 36 and potential as a drug to treat sleep disorders such as insomnia.…”

“…The effects of these three compounds on wakefulness were evaluated in sleep experiments with mice via electroencephalogram/electromyogram (EEG/EMG) recordings during the first 3 h of the dark phase, as shown in Figure 3. 36 All compounds elicited a significant reduction in the time of wakefulness following an oral dose of 30 mg/kg ( Figure 3). Because of its well-balanced in vitro profiles taking into account the in vitro binding affinity, solubility, and other parameters, compound 26 was selected for optimization of the C ring.…”

“…According to our previous work, the methoxy groups are critical pharmacophores; the orientations of the small lipophilic group and lone pair were shown to strongly influence in vitro binding affinity. 36 On the basis of the information regarding 3,4-di-OMe-Ph in the Cambridge Structural Database (CSD), the Me groups face opposite directions ( Figure 2). Therefore, two types of dimethylpyridines (50 and 51) were designed with the hope of imitating the pharmacophores of 3,4-di-OMe-Ph, the lone pair and small lipophilic group (Table 2).…”

“…36 As a consequence, increased Pgp susceptibility was observed in 3-and 4-pyridine-containing Table 2. A-Ring Modifications: Compounds 50−53 and 19−22 derivatives (24 and 25, respectively), with a close resemblance to previously identified SARs involving the derivatization of the di-OMe phenyl series.…”

“…A-Ring Modifications: Compounds 50−53 and 19−22 derivatives (24 and 25, respectively), with a close resemblance to previously identified SARs involving the derivatization of the di-OMe phenyl series. 36 Subsequently, we evaluated the SARs of 2-pyridine-containing moieties in the B-ring, with the aim of enhancing the in vitro binding affinity and in vivo efficacy without adversely affecting other parameters. Introduction of substituents in the 5-position, such as in compounds 26 and 28, resulted in a greater in vitro binding affinity than that of 23.…”