From Oxadiazole to Triazole Analogues: Optimization toward a Dual Orexin Receptor Antagonist with Improved in vivo Efficacy in Dogs

The orexin system is responsible for regulating the sleep-wake cycle. Suvorexant, a dual orexin receptor antagonist (DORA) is approved by the FDA for the treatment of insomnia disorders. Herein, we report the optimization efforts toward a DORA, where our starting point was (5-methoxy-4-methyl-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-[5-(2-trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-pyrrolidin-1-yl}methanone ( 6 ), a compound which emerged from our in-house research program. Compound 6 was shown to be a potent, brain-penetrating DORA with in vivo efficacy similar to suvorexant in rats. However, shortcomings from low metabolic stability, high plasma protein binding (PPB), low brain free fraction (f_u brain), and low aqueous solubility, were identified and hence, compound 6 was not an ideal candidate for further development. Our optimization efforts addressing the above-mentioned shortcomings resulted in the identification of (4-chloro-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-methyl-2-[5-(2-trifluoromethoxy-phenyl)-4H-[1,2,4]triazol-3-yl]-pyrrolidin-1-yl}l-methanone ( 42 ), a DORA with improved in vivo efficacy compared to 6 .     

Sleep Disorders Reduce Health-Related Quality of Life in Multiple Sclerosis (Nottingham Health Profile Data in Patients with Multiple Sclerosis)

Quality of Life (QoL) is decreased in multiple sclerosis (MS), but studies about the impact of sleep disorders (SD) on health-related quality of Life (HRQoL) are lacking. From our original cohort, a cross-sectional polysomnographic (PSG) study in consecutive MS patients, we retrospectively analysed the previously unpublished data of the Nottingham Health Profile (NHP). Those MS patients suffering from sleep disorders (n = 49) showed significantly lower HRQoL compared to MS patients without sleep disorders (n = 17). Subsequently, we classified the patients into four subgroups: insomnia (n = 17), restless-legs syndrome, periodic limb movement disorder and SD due to leg pain (n = 24), obstructive sleep apnea (n = 8) and patients without sleep disorder (n = 17). OSA and insomnia patients showed significantly higher NHP values and decreased HRQoL not only for the sleep subscale but also for the “energy” and “emotional” area of the NHP. In addition, OSA patients also showed increased NHP values in the “physical abilities” area. Interestingly, we did not find a correlation between the objective PSG parameters and the subjective sleep items of the NHP. However, this study demonstrates that sleep disorders can reduce HRQoL in MS patients and should be considered as an important confounder in all studies investigating HRQoL in MS.     

Discovery of 5′′‐Chloro‐N‐[(5,6‐dimethoxypyridin‐2‐yl)methyl]‐2,2′:5′,3′′‐terpyridine‐3′‐carboxamide (MK‐1064): A Selective Orexin 2 Receptor Antagonist (2‐SORA) for the Treatment of Insomnia

The field of small‐molecule orexin antagonist research has evolved rapidly in the last 15 years from the discovery of the orexin peptides to clinical proof‐of‐concept for the treatment of insomnia. Clinical programs have focused on the development of antagonists that reversibly block the action of endogenous peptides at both the orexin 1 and orexin 2 receptors (OX₁R and OX₂R), termed dual orexin receptor antagonists (DORAs), affording late‐stage development candidates including Merck’s suvorexant (new drug application filed 2012). Full characterization of the pharmacology associated with antagonism of either OX₁R or OX₂R alone has been hampered by the dearth of suitable subtype‐selective, orally bioavailable ligands. Herein, we report the development of a selective orexin 2 antagonist (2‐SORA) series to afford a potent, orally bioavailable 2‐SORA ligand. Several challenging medicinal chemistry issues were identified and overcome during the development of these 2,5‐disubstituted nicotinamides, including reversible CYP inhibition, physiochemical properties, P‐glycoprotein efflux and bioactivation. This article highlights structural modifications the team utilized to drive compound design, as well as in vivo characterization of our 2‐SORA clinical candidate, 5′′‐chloro‐N‐[(5,6‐dimethoxypyridin‐2‐yl)methyl]‐2,2′:5′,3′′‐terpyridine‐3′‐carboxamide (MK‐1064), in mouse, rat, dog, and rhesus sleep models.     

慢性失眠临床诊断与药物治疗研究现状

慢性失眠的临床症状较为多样,临床诊断过程需要结合患者的睡眠参数和日间症状进行综合分析,同时还要注意关注患者的精神心理状况。近年来,神经影像学的研究内容提示慢性失眠患者存在一定的中枢功能和结构方面的改变,为后续的研究提供了新的方向。针对慢性失眠治疗的新型药物中,一部分侧重提高受体专一性以降低副反应的发生率,一部分增加干预作用靶点以达到改善睡眠和调节情绪等多方面效果,为慢性失眠患者临床治疗提供了更多的选择。     

Efficacy of two behavioral treatment programs for comorbid geriatric insomnia.

Older adults with comorbid insomnia and medical illness have been excluded from behavioral treatment research, but recent evidence suggested that such treatments would be effective with this population. In this study, 38 older adults with comorbid insomnia were randomized to 1 of 3 conditions: classroom cognitive-behavioral treatment (CBT), home-based audio relaxation treatment (HART), or delayed-treatment control. Compared to the control group, the CBT group had significant changes in 5 of 7 self-report measures of sleep at the 4-month follow-up. The HART group obtained significant outcomes on 3 of 7 measures. Wrist actigraphy measures and secondary-outcome measures did not yield significant findings for either treatment. Clinically significant changes at follow-up were obtained for 54% of patients in CBT, 35% in HART, and 6% in the control group when treatment dropouts were included. Although not as effective as in-person CBT, home interventions may have utility as a first-line, low-cost treatment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Relaxation and sleep compression for late-life insomnia: A placebo-controlled trial.

Older adults with insomnia were recruited from the community and randomized to treatments: relaxation, sleep compression, and placebo desensitization. Questionnaire data collected at baseline, posttreatment, and 1-year follow-up and polysomnography data collected at baseline and follow-up yielded the following conclusions: All treatments improved self-reported sleep, but objective sleep was unchanged. Clinical significance analyses yielded the strongest findings supporting the active treatments and suggested that sleep compression was most effective. Results partially supported the conclusion that individuals with high daytime impairment (i.e., fatigue) respond best to treatments that extend sleep, as in relaxation, and individuals with low daytime impairment respond best to treatments that consolidate sleep, as in sleep compression. Strong methodological features including a placebo condition and a treatment implementation scheme elevate the confidence due these findings. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Self-Efficacy and Compliance With Benzodiazepine Taper in Older Adults With Chronic Insomnia.

Better understanding of compliance with BZD taper is warranted. Compliance with a taper program and perceived self-efficacy (SE) in being able to comply with hypnotic reduction goals was monitored weekly in 52 older adults (mean age: 63.0 years) with chronic insomnia (average duration: 21.9 years) who underwent a 10-week physician-supervised medication tapering. One group received cognitive- behavior therapy for insomnia during discontinuation, whereas the other did not. Compliant patients showed higher SE ratings at Weeks 6, 8, 9, and 10. Medication-free patients at the end of the treatment also reported higher mean SE ratings at those 4 weeks. Differences remained significant when withdrawal symptoms and sleep efficiency were controlled for. These results have important clinical implications because SE may indicate key time points when patients are experiencing more difficulty during discontinuation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Hypnotic taper with or without self-help treatment of insomnia: A randomized clinical trial.

This study aimed to assess the efficacy of a minimal intervention focusing on hypnotic discontinuation and cognitive-behavioral treatment (CBT) for insomnia. Fifty-three adult chronic users of hypnotics were randomly assigned to an 8-week hypnotic taper program, used alone or combined with a self-help CBT. Weekly hypnotic use decreased in both conditions, from a nearly nightly use at baseline to less than once a week at posttreatment. Nightly dosage (in lorazepam equivalent) decreased from 1.67 mg to 0.12 mg. Participants who received CBT improved their sleep efficiency by 8%, whereas those who did not remained stable. Total wake time decreased by 52 min among CBT participants and increased by 13 min among those receiving the taper schedule alone. Total sleep time remained stable throughout withdrawal in both CBT and taper conditions. The present findings suggest that a systematic withdrawal schedule might be sufficient in helping chronic users stop their hypnotic medication. The addition of a self-help treatment focusing on insomnia, a readily available and cost-effective alternative to individual psychotherapy, produced greater sleep improvement. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Assessment and treatment of sleep disorders in older adults: A review for rehabilitation psychologists.

Recent research has led to significant progress in the assessment and treatment of sleep disturbance in older adults. Similar advances have been made with sleep disorders secondary to age-related chronic illness. The assessment and treatment of sleep disorders encompasses numerous behavioral aspects. Thus, rehabilitation psychologists are ideally positioned to help apply these new advances to the growing number of older adult patients in the rehabilitation setting. The authors provide an overview of age and disease-related sleep disorders. They provide details for implementation of behavioral treatments for geriatric insomnia that is comorbid with chronic illness. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Barriers to engagement in sleep restriction and stimulus control in chronic insomnia.

Sleep restriction (SRT) and stimulus control (SC) have been found to be effective interventions for chronic insomnia (Morgenthaler et al., 2006), and yet adherence to SRT and SC varies widely. The objective of this study was to investigate correlates to adherence to SC/SRT among 40 outpatients with primary or comorbid insomnia using a correlational design. Participants completed a self-report measure of sleepiness prior to completion of a 6-week cognitive behavioral treatment group for insomnia. At the posttreatment period, they rated their ability to engage in SC/SRT using a survey. Results from standard multiple regression analyses showed that perceiving fewer barriers (i.e., less boredom, annoyance) to engaging in SC/SRT and experiencing less pretreatment sleepiness were each associated with better adherence to SC/SRT. Adherence to SC/SRT was associated with outcome. Implications of these findings are that more work is needed to make SC/SRT less uncomfortable, possibly by augmenting energy levels prior to introducing these approaches. (PsycINFO Database Record (c) 2010 APA, all rights reserved)