Disposition and Metabolism of [<sup>14</sup>C]SB-649868, an Orexin 1 and 2 Receptor Antagonist, in Humans

Renzulli, Cecilia; Nash, Mike; Wright, Mark; Thomas, Steven R.; Zamuner, Stefano; Pellegatti, Mario; Bettica, Paolo; Boyle, Gary

doi:10.1124/dmd.110.035386

Cited by 27 publications

(18 citation statements)

References 14 publications

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“…This effect appeared to be dose-related, being less than a 20% increase at 5 mg and 15 mg doses and approximately 30-40% at the 30 mg dose. A dose-and time-dependent increase in exposure to concomitantly administered simvastatin was also observed, suggesting inhibition of CYP3A4 by SB-649868 which was mild (50% increase in simvastatin) at a dose of 5 mg, moderate (200-300% increase) at 15 mg and strong (200-500% increase) at 30 mg. SB-649868 is primarily metabolized by CYP3A4 enzymes (Renzulli et al, 2011) and these findings are consistent with the in vitro and preclinical data. In unpublished in vitro studies using human liver microsomes, SB-649868 competitively inhibited CYP3A, with IC 50 values of 0.36, 0.38 and 2.9 mM against the probe substrates atorvastatin, midazolam and nifedipine.…”

Section: Discussionsupporting

confidence: 87%

Phase I studies on the safety, tolerability, pharmacokinetics and pharmacodynamics of SB-649868, a novel dual orexin receptor antagonist

et al. 2011

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The orexin system plays a major role in the integration of metabolic and circadian influences that drive wakefulness. This paper describes initial Phase I trials of a novel dual orexin receptor antagonist SB-649868 that has demonstrated preclinical potential for treatment of sleep disorders. The trial designs included a single ascending dose escalation study (dose range: 10-80 mg in the fed and fasted states) and a multiple repeat dose study (dose range: 5-30 mg in the fed state) enrolling a total of 103 male volunteer subjects. SB-649868 was well tolerated at all doses in this study population, with mechanism-related adverse events (e.g. somnolence and fatigue) observed in a majority of subjects after 60 and 80 mg single doses. Although total drug exposure was similar in the fed and fasted states, the rate, but not the extent, of absorption increased in the fed state, resulting in an increased C(max). The typical estimated half-life of SB-649868 was 3-6 h - comparable with currently used hypnotic agents. Repeated administration of SB-649868 dose-dependently increased exposure to simvastatin (10 mg), suggesting CYP3A4 inhibition ranging from very mild (5 mg) to strong (30 mg). Evening dosing resulted in significant dose-dependent improvement in latency to persistent sleep, total sleep time and wake after sleep onset as measured by polysomnography. Next-morning testing did not detect evidence of residual cognitive effects. Results of these trials support further investigation of SB-649868 and other dual orexin receptor antagonists as potentially effective and well-tolerated treatments for patients with sleep disorders.

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Section: Discussionsupporting

confidence: 87%

Phase I studies on the safety, tolerability, pharmacokinetics and pharmacodynamics of SB-649868, a novel dual orexin receptor antagonist

et al. 2011

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“…The fragmentation patterns of other amphetamines or benzofurans [4,11] and the general fragmentation rules described by, e.g., Smith and Bush or McLafferty were taken into consideration [19,20]. Furthermore, the metabolism of other furan or benzofuran containing compounds was considered [21][22][23][24][25][26][27]. Figure 1 shows the EI mass spectra, structures, predominant fragmentation patterns, and GC retention indices (RI) of the acetylated parent compounds and their acetylated metabolites (1.1-1.11).…”

Section: Gc-ms Identification Of Phase I Metabolitesmentioning

confidence: 99%

Benzofuran analogues of amphetamine and methamphetamine: studies on the metabolism and toxicological analysis of 5-APB and 5-MAPB in urine and plasma using GC-MS and LC-(HR)-MSn techniques

et al. 2014

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5-APB (5-(2-aminopropyl)benzofuran) and its N-methyl derivative 5-MAPB (N-methyl-5-(2-aminopropyl)benzofuran) are analogues of amphetamine and methamphetamine, respectively, and belong to the so-called novel psychoactive substances (NPS). They were consumed as stimulants or entactogens with euphoric and empathogenic effects. Being controlled in some countries, both compounds should be covered by drug testing in clinical and forensic toxicology. Therefore, metabolism studies have been performed by working up rat urine samples after a high single dose of the corresponding NPS with solid-phase extraction without and after enzymatic conjugates cleavage. The phase I metabolites were separated and identified after acetylation by GC-MS and/or LC-HR-MS(n) and the phase II metabolites by LC-HR-MS(n). The main metabolite of 5-APB was 3-carboxymethyl-4-hydroxy amphetamine and the main metabolites of 5-MAPB were 5-APB (N-demethyl metabolite) and 3-carboxymethyl-4-hydroxy methamphetamine. The cytochrome P450 (CYP) isoenzymes involved in the 5-MAPB N-demethylation were CYP1A2, CYP2B6, CYP2C19, and CYP2D6, and according to the kinetic parameters, CYP2B6 was responsible for the main part of the total CYP-dependent clearance. An intake of a common users' dose of 5-APB or 5-MAPB could be confirmed in rat urine using the authors' GC-MS and the LC-MS(n) standard urine screening approaches with the corresponding parent drugs as major target. In authentic human urine samples after ingestion of unknown doses of 5-MAPB, both metabolites could also be detected besides the parent drug. The plasma concentrations determined in six clinical cases ranged from 5 to 124 μg/L for 5-MAPB and from 1 to 38 μg/L for its N-demethyl metabolite 5-APB.

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“…Indeed, at least three pharmaceutical companies (GSK, MERCK, Actelion) have initiated clinical trials investigating the utility of DORAs in modulating the sleep-wake cycle. These DORAs include almorexant (ACT-078573; Brisbare-Roch et al, 2007 ; Malherbe et al, 2009b ); suvorexant (MK-4305; Cox et al, 2010 ), Merck DORA-1 (Bergman et al, 2008 ), Merck DORA-5 (Whitman et al, 2009 ), and SB-649868 (Renzulli et al, 2011 ). Only a limited number of studies have examined the effects of DORAs on addiction-related behaviors, with this work focusing almost exclusively on almorexant.…”

Section: Effects Of Soras and Doras On Drug-seeking Behaviorsmentioning

confidence: 99%

Orexin antagonists for neuropsychiatric disease: progress and potential pitfalls

Yeoh¹,

Campbell²,

James³

et al. 2014

Front. Neurosci.

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The tight regulation of sleep/wake states is critical for mental and physiological wellbeing. For example, dysregulation of sleep/wake systems predisposes individuals to metabolic disorders such as obesity and psychiatric problems, including depression. Contributing to this understanding, the last decade has seen significant advances in our appreciation of the complex interactions between brain systems that control the transition between sleep and wake states. Pivotal to our increased understanding of this pathway was the description of a group of neurons in the lateral hypothalamus (LH) that express the neuropeptides orexin A and B (hypocretin, Hcrt-1 and Hcrt-2). Orexin neurons were quickly placed at center stage with the demonstration that loss of normal orexin function is associated with the development of narcolepsy—a condition in which sufferers fail to maintain normal levels of daytime wakefulness. Since these initial seminal findings, much progress has been made in our understanding of the physiology and function of the orexin system. For example, the orexin system has been identified as a key modulator of autonomic and neuroendocrine function, arousal, reward and attention. Notably, studies in animals suggest that dysregulation of orexin function is associated with neuropsychiatric states such as addiction and mood disorders including depression and anxiety. This review discusses the progress associated with therapeutic attempts to restore orexin system function and treat neuropsychiatric conditions such as addiction, depression and anxiety. We also highlight potential pitfalls and challenges associated with targeting this system to treat these neuropsychiatric states.

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Disposition and Metabolism of [¹⁴C]SB-649868, an Orexin 1 and 2 Receptor Antagonist, in Humans

Cited by 27 publications

References 14 publications

Phase I studies on the safety, tolerability, pharmacokinetics and pharmacodynamics of SB-649868, a novel dual orexin receptor antagonist

Phase I studies on the safety, tolerability, pharmacokinetics and pharmacodynamics of SB-649868, a novel dual orexin receptor antagonist

Benzofuran analogues of amphetamine and methamphetamine: studies on the metabolism and toxicological analysis of 5-APB and 5-MAPB in urine and plasma using GC-MS and LC-(HR)-MSn techniques

Orexin antagonists for neuropsychiatric disease: progress and potential pitfalls

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Disposition and Metabolism of [14C]SB-649868, an Orexin 1 and 2 Receptor Antagonist, in Humans

Cited by 27 publications

References 14 publications

Phase I studies on the safety, tolerability, pharmacokinetics and pharmacodynamics of SB-649868, a novel dual orexin receptor antagonist

Phase I studies on the safety, tolerability, pharmacokinetics and pharmacodynamics of SB-649868, a novel dual orexin receptor antagonist

Benzofuran analogues of amphetamine and methamphetamine: studies on the metabolism and toxicological analysis of 5-APB and 5-MAPB in urine and plasma using GC-MS and LC-(HR)-MSn techniques

Orexin antagonists for neuropsychiatric disease: progress and potential pitfalls

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Product

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Disposition and Metabolism of [¹⁴C]SB-649868, an Orexin 1 and 2 Receptor Antagonist, in Humans