SB-649868 - CAS 380899-24-1
Category: Inhibitor
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Molecular Formula:
Molecular Weight:
Orexin Receptor (OX Receptor)
SB-649868 is a novel, orally active dual orexin receptor antagonist of orexin(OX)1 and OX2 receptor (pKi=9.4 and 9.5 at the OX1 and OX2 receptor, respectively), potentially for the treatment of insomnia and sleep disorder.
N-[[(2S)-1-[5-(4-fluorophenyl)-2-methyl-1,3-thiazole-4-carbonyl]piperidin-2-yl]methyl]-1-benzofuran-4-carboxamide; (14C)SB 649868; (14C)SB-649868; (14C)SB649868; N-((1-((5-(4-fluorophenyl)-2-methyl-4-thiazolyl)carbonyl)-2-piperidinyl)methyl)-4-benzofurancarboxamide; SB 649868; SB-649868; SB649868; GSK-649868; GSK-649868; GSK649868
Store in a cool and dry place (or refer to the Certificate of Analysis).
Boiling Point:
725.1±55.0 ℃ at 760 Torr
1.305±0.06 g/cm3
Canonical SMILES:
1.Neuroendocrine and sympathetic responses to an orexin receptor antagonist, SB-649868, and alprazolam following insulin-induced hypoglycemia in humans.
Patel AX;Miller SR;Nathan PJ;Kanakaraj P;Napolitano A;Lawrence P;Koch A;Bullmore ET Psychopharmacology (Berl). 2014 Oct;231(19):3817-28. doi: 10.1007/s00213-014-3520-7. Epub 2014 Apr 26.
RATIONALE: ;The orexin-hypocretin system is important for translating peripheral metabolic signals and central neuronal inputs to a diverse range of behaviors, from feeding, motivation and arousal, to sleep and wakefulness. Orexin signaling is thus an exciting potential therapeutic target for disorders of sleep, feeding, addiction, and stress.;OBJECTIVES/METHODS: ;Here, we investigated the low dose pharmacology of orexin receptor antagonist, SB-649868, on neuroendocrine, sympathetic nervous system, and behavioral responses to insulin-induced hypoglycemic stress, in 24 healthy male subjects (aged 18-45 years; BMI 19.0-25.9 kg/m(2)), using a randomized, double-blind, placebo-controlled, within-subject crossover design. Alprazolam, a licensed benzodiazepine anxiolytic, was used as a positive comparator, as it has previously been validated using the insulin tolerance test (ITT) model in humans.;RESULTS: ;Of the primary endpoints, ITT induced defined increases in pulse rate, plasma cortisol, and adrenocorticotropic hormone in the placebo condition, but these responses were not significantly impacted by alprazolam or SB-649868 pre-treatment. Of the secondary endpoints, ITT induced a defined increase in plasma concentrations of adrenaline, noradrenaline, growth hormone (GH), and prolactin in the placebo condition.
2.Selective Inhibition of Orexin-2 Receptors Prevents Stress-Induced ACTH Release in Mice.
Yun S;Wennerholm M;Shelton JE;Bonaventure P;Letavic MA;Shireman BT;Lovenberg TW;Dugovic C Front Behav Neurosci. 2017 May 8;11:83. doi: 10.3389/fnbeh.2017.00083. eCollection 2017.
Orexins peptides exert a prominent role in arousal-related processes including stress responding, by activating orexin-1 (OX1R) and orexin-2 (OX2R) receptors located widely throughout the brain. Stress or orexin administration stimulates hyperarousal, adrenocorticotropic hormone (ACTH) and corticosterone release, and selective OX1R blockade can attenuate several stress-induced behavioral and cardiovascular responses but not the hypothalamic-pituitary-adrenal (HPA) axis activation. As opposed to OX1R, OX2R are preferentially expressed in the paraventricular hypothalamic nucleus which is involved in the HPA axis regulation. In the present study, we investigated the effects of a psychological stress elicited by cage exchange (CE) on ACTH release in two murine models (genetic and pharmacological) of selective OX2R inhibition. CE-induced stress produced a significant increase in ACTH serum levels. Mice lacking the OX2R exhibited a blunted stress response. Stress-induced ACTH release was absent in mice pre-treated with the selective OX2R antagonist JNJ-42847922 (30 mg/kg po), whereas pre-treatment with the dual OX1/2R antagonist SB-649868 (30 mg/kg po) only partially attenuated the increase of ACTH.
3.Discovery and development of orexin receptor antagonists as therapeutics for insomnia.
Winrow CJ;Renger JJ Br J Pharmacol. 2014 Jan;171(2):283-93. doi: 10.1111/bph.12261.
Insomnia persistently affects the quality and quantity of sleep. Currently approved treatments for insomnia primarily target γ-aminobutyric acid-A (GABA-A) receptor signalling and include benzodiazepines and GABA-A receptor modulators. These drugs are used to address this sleep disorder, but have the potential for side effects such as tolerance and dependence, making them less attractive as maintenance therapy. Forward and reverse genetic approaches in animals have implicated orexin signalling (also referred to as hypocretin signalling) in the control of vigilance and sleep/wake states. Screening for orexin receptor antagonists using in vitro and in vivo methods in animals has identified compounds that block one or other of the orexin receptors (single or dual orexin receptor antagonists [SORAs and DORAs], respectively) in animals and humans. SORAs have primarily been used as probes to further elucidate the roles of the individual orexin receptors, while a number of DORAs have progressed to clinical development as pharmaceutical candidates for insomnia. The DORA almorexant demonstrated significant improvements in a number of clinically relevant sleep parameters in animal models and in patients with insomnia but its development was halted.
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CAS 380899-24-1 SB-649868

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