SB-334867

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SB-334867
SB-334,867.svg
Identifiers
  • 1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-yl urea
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.164.490 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C17H13N5O2
Molar mass 319.324 g·mol−1
3D model (JSmol)
  • O=C(Nc1c2ncccc2ncc1)Nc3ccc4nc(oc4c3)C
  • InChI=1S/C17H13N5O2/c1-10-20-12-5-4-11(9-15(12)24-10)21-17(23)22-14-6-8-18-13-3-2-7-19-16(13)14/h2-9H,1H3,(H2,18,21,22,23) Yes check.svgY
  • Key:AKMNUCBQGHFICM-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

SB-334867 is an orexin antagonist. It was the first non-peptide antagonist developed that is selective for the orexin receptor subtype OX1, with around 50x selectivity for OX1 over OX2 receptors. [1] It has been shown to produce sedative and anorectic effects in animals, [2] and has been useful in characterising the orexinergic regulation of brain systems involved with appetite and sleep, [3] [4] [5] [6] [7] [8] as well as other physiological processes. [9] [10] [11] [12] The hydrochloride salt of SB-334867 has been demonstrated to be hydrolytically unstable, both in solution and as the solid. [13] Orexin antagonists have multiple potential clinical applications including the treatment of drug addiction, insomnia, obesity and diabetes. [14] [15] [16] [17] [18] [19] [20] [21]

Related Research Articles

<span class="mw-page-title-main">Orexin</span> Neuropeptide that regulates arousal, wakefulness, and appetite.

Orexin, also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. The most common form of narcolepsy, type 1, in which the individual experiences brief losses of muscle tone, is caused by a lack of orexin in the brain due to destruction of the cells that produce it. It exists in the forms of orexin-A and orexin-B.

<span class="mw-page-title-main">Dopaminergic pathways</span> Projection neurons in the brain that synthesize and release dopamine

Dopaminergic pathways in the human brain are involved in both physiological and behavioral processes including movement, cognition, executive functions, reward, motivation, and neuroendocrine control. Each pathway is a set of projection neurons, consisting of individual dopaminergic neurons.

<span class="mw-page-title-main">5-HT receptor</span> Class of transmembrane proteins

5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neurotransmission. The serotonin receptors are activated by the neurotransmitter serotonin, which acts as their natural ligand.

<span class="mw-page-title-main">Endocannabinoid system</span> Biological system of neurotransmitters

The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors, and cannabinoid receptor proteins that are expressed throughout the vertebrate central nervous system and peripheral nervous system. The endocannabinoid system remains under preliminary research, but may be involved in regulating physiological and cognitive processes, including fertility, pregnancy, pre- and postnatal development, various activity of immune system, appetite, pain-sensation, mood, and memory, and in mediating the pharmacological effects of cannabis. The ECS plays an important role in multiple aspects of neural functions, including the control of movement and motor coordination, learning and memory, emotion and motivation, addictive-like behavior and pain modulation, among others.

<span class="mw-page-title-main">Lateral hypothalamus</span>

The lateral hypothalamus (LH), also called the lateral hypothalamic area (LHA), contains the primary orexinergic nucleus within the hypothalamus that widely projects throughout the nervous system; this system of neurons mediates an array of cognitive and physical processes, such as promoting feeding behavior and arousal, reducing pain perception, and regulating body temperature, digestive functions, and blood pressure, among many others. Clinically significant disorders that involve dysfunctions of the orexinergic projection system include narcolepsy, motility disorders or functional gastrointestinal disorders involving visceral hypersensitivity, and eating disorders.

The orexin receptor (also referred to as the hypocretin receptor) is a G-protein-coupled receptor that binds the neuropeptide orexin. There are two variants, OX1 and OX2, each encoded by a different gene (HCRTR1, HCRTR2).

<span class="mw-page-title-main">SB-277,011-A</span> Chemical compound

SB-277,011A is a drug which acts as a potent and selective dopamine D3 receptor antagonist, which is around 80-100x selective for D3 over D2, and lacks any partial agonist activity.

<span class="mw-page-title-main">Hypocretin (orexin) receptor 1</span> Protein-coding gene in the species Homo sapiens

Orexin receptor type 1 (Ox1R or OX1), also known as hypocretin receptor type 1 (HcrtR1), is a protein that in humans is encoded by the HCRTR1 gene.

<span class="mw-page-title-main">Hypocretin (orexin) receptor 2</span> Protein-coding gene in the species Homo sapiens

Orexin receptor type 2 (Ox2R or OX2), also known as hypocretin receptor type 2 (HcrtR2), is a protein that in humans is encoded by the HCRTR2 gene.

5-HT<sub>6</sub> receptor Protein-coding gene in the species Homo sapiens

The 5HT6 receptor is a subtype of 5HT receptor that binds the endogenous neurotransmitter serotonin (5-hydroxytryptamine, 5HT). It is a G protein-coupled receptor (GPCR) that is coupled to Gs and mediates excitatory neurotransmission. HTR6 denotes the human gene encoding for the receptor.

Orexin-A, also known as hypocretin-1, is a naturally occurring neuropeptide and orexin isoform. The orexinergic nucleus in the lateral hypothalamus is the primary orexin projection system in the brain.

<span class="mw-page-title-main">Almorexant</span> Chemical compound

Almorexant, also known by its development code ACT-078573, is an orexin antagonist, acting as a competitive antagonist of the OX1 and OX2 orexin receptors, which was being developed by the pharmaceutical companies Actelion and GSK for the treatment of insomnia. Development of the drug was abandoned in January 2011 due to concerns over the hepatic safety of almorexant after transient increases in liver enzymes were observed in trials.

<span class="mw-page-title-main">SB-271046</span> Chemical compound

SB-271046 is a drug which is used in scientific research. It was one of the first selective 5-HT6 receptor antagonists to be discovered, and was found through high-throughput screening of the SmithKline Beecham Compound Bank using cloned 5-HT6 receptors as a target, with an initial lead compound being developed into SB-271046 through a structure-activity relationship (SAR) study. SB-271046 was found to be potent and selective in vitro and had good oral bioavailability in vivo, but had poor penetration across the blood–brain barrier, so further SAR work was then conducted, which led to improved 5-HT6 antagonists such as SB-357,134 and SB-399,885.

<span class="mw-page-title-main">SB-216641</span> Chemical compound

SB-216641 is a drug which is a selective antagonist for the serotonin receptor 5-HT1B, with around 25x selectivity over the closely related 5-HT1D receptor. It is used in scientific research, and has demonstrated anxiolytic effects in animal studies.

<span class="mw-page-title-main">SB-408124</span> Chemical compound

SB-408124 is a drug which is a non-peptide antagonist selective for the orexin receptor subtype OX1, with around 70x selectivity for OX1 over OX2 receptors, and improved oral bioavailability compared to the older OX1 antagonist SB-334867. It is used in scientific research into the function of orexinergic neurons in the body.

<span class="mw-page-title-main">Suvorexant</span> Medication used to treat insomnia

Suvorexant, sold under the brand name Belsomra, is an orexin antagonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset and/or maintenance in adults. Suvorexant helps with falling asleep faster, sleeping longer, being awake less in the middle of the night, and having better quality of sleep. Its effectiveness is modest, and is similar to that of other orexin antagonists, but is lower than that of benzodiazepines and Z-drugs. Suvorexant is taken by mouth.

An orexin receptor antagonist, or orexin antagonist, is a drug that inhibits the effect of orexin by acting as a receptor antagonist of one (selective orexin receptor antagonist or SORA) or both (dual orexin receptor antagonis or DORA) of the orexin receptors, OX1 and OX2. Medical applications include treatment of sleep disorders such as insomnia.

<span class="mw-page-title-main">Filorexant</span> Chemical compound

Filorexant (INNTooltip International Nonproprietary Name, USANTooltip United States Approved Name; developmental code name MK-6096) is an orexin antagonist which was under development by Merck for the treatment of insomnia, depression, diabetic neuropathy, and migraine. It is a dual antagonist of the orexin OX1 and OX2 receptors. It has a relatively short elimination half-life of 3 to 6 hours. However, it dissociates slowly from the orexin receptors and may thereby have a longer duration. Possibly in relation to this, filorexant shows next-day somnolence similarly to suvorexant. In phase 2 clinical trials, filorexant was found to be effective in the treatment of insomnia, but was not effective in the treatment of major depressive disorder, painful diabetic neuropathy, or migraine. As of May 2015, filorexant was no longer listed on Merck's online development pipeline and hence development of the drug appears to have been discontinued. Development of filorexant may have been discontinued due to lack of differentiation from suvorexant (which was also developed by Merck).

<span class="mw-page-title-main">Seltorexant</span> Experimental anti-insomnia drug

Seltorexant, also known by its developmental code names MIN-202 and JNJ-42847922, is an orexin antagonist medication which is under development for the treatment of depression and insomnia. It is a selective antagonist of the orexin OX2 receptor (2-SORA). The medication is taken by mouth. As of February 2022, seltorexant is in phase 3 clinical trials for treatment of major depressive disorder (MDD) and phase 2 trials for treatment of insomnia. It was also under investigation for the treatment of sleep apnea, but no recent development has been reported for this indication. Seltorexant is under development by Minerva Neurosciences and Johnson & Johnson's Janssen Pharmaceuticals.

<span class="mw-page-title-main">ACT-539313</span> Chemical compound

ACT-539313 is an orexin antagonist medication which is under development for the treatment of binge eating disorder and was previously under development for the treatment of anxiety disorders. It is an orally active small-molecule compound with an elimination half-life of 3.3 to 6.5 hours and acts as a selective orexin OX1 receptor antagonist (1-SORA). As of May 2022, the drug is in phase 2 clinical trials for binge eating disorder. Following negative efficacy results of a phase 2 trial of ACT-539313 for binge eating disorder, Idorsia (the developer of ACT-539313) signaled in May 2022 that it would not pursue further development of the drug for this indication.

References

  1. ↑ Smart D, Sabido-David C, Brough SJ, Jewitt F, Johns A, Porter RA, Jerman JC (March 2001). "SB-334867-A: the first selective orexin-1 receptor antagonist". British Journal of Pharmacology. 132 (6): 1179–82. doi:10.1038/sj.bjp.0703953. PMC   1572677 . PMID   11250867.
  2. ↑ Rodgers RJ, Halford JC, Nunes de Souza RL, Canto de Souza AL, Piper DC, Arch JR, et al. (April 2001). "SB-334867, a selective orexin-1 receptor antagonist, enhances behavioural satiety and blocks the hyperphagic effect of orexin-A in rats". The European Journal of Neuroscience. 13 (7): 1444–52. doi:10.1046/j.0953-816x.2001.01518.x. PMID   11298806. S2CID   24935644.
  3. ↑ Haynes AC, Chapman H, Taylor C, Moore GB, Cawthorne MA, Tadayyon M, et al. (March 2002). "Anorectic, thermogenic and anti-obesity activity of a selective orexin-1 receptor antagonist in ob/ob mice". Regulatory Peptides. 104 (1–3): 153–9. doi:10.1016/S0167-0115(01)00358-5. PMID   11830290. S2CID   25523175.
  4. ↑ Rodgers RJ, Ishii Y, Halford JC, Blundell JE (October 2002). "Orexins and appetite regulation". Neuropeptides. 36 (5): 303–25. doi:10.1016/S0143-4179(02)00085-9. PMID   12450737. S2CID   23352886.
  5. ↑ Bernard R, Lydic R, Baghdoyan HA (October 2003). "Hypocretin-1 causes G protein activation and increases ACh release in rat pons" (PDF). The European Journal of Neuroscience. 18 (7): 1775–85. doi:10.1046/j.1460-9568.2003.02905.x. hdl: 2027.42/75751 . PMID   14622212. S2CID   18515164.
  6. ↑ Soffin EM, Gill CH, Brough SJ, Jerman JC, Davies CH (June 2004). "Pharmacological characterisation of the orexin receptor subtype mediating postsynaptic excitation in the rat dorsal raphe nucleus". Neuropharmacology. 46 (8): 1168–76. doi:10.1016/j.neuropharm.2004.02.014. PMID   15111023. S2CID   45872346.
  7. ↑ Thorpe AJ, Kotz CM (July 2005). "Orexin A in the nucleus accumbens stimulates feeding and locomotor activity". Brain Research. 1050 (1–2): 156–62. doi:10.1016/j.brainres.2005.05.045. PMID   15979595. S2CID   24662237.
  8. ↑ Frederick-Duus D, Guyton MF, Fadel J (November 2007). "Food-elicited increases in cortical acetylcholine release require orexin transmission". Neuroscience. 149 (3): 499–507. doi:10.1016/j.neuroscience.2007.07.061. PMID   17928158. S2CID   19452926.
  9. ↑ Small CJ, Goubillon ML, Murray JF, Siddiqui A, Grimshaw SE, Young H, et al. (July 2003). "Central orexin A has site-specific effects on luteinizing hormone release in female rats". Endocrinology. 144 (7): 3225–36. doi: 10.1210/en.2002-0041 . PMID   12810579.
  10. ↑ D'Anna KL, Gammie SC (August 2006). "Hypocretin-1 dose-dependently modulates maternal behaviour in mice". Journal of Neuroendocrinology. 18 (8): 553–66. doi:10.1111/j.1365-2826.2006.01448.x. PMC   2275401 . PMID   16867176.
  11. ↑ Muschamp JW, Dominguez JM, Sato SM, Shen RY, Hull EM (March 2007). "A role for hypocretin (orexin) in male sexual behavior". The Journal of Neuroscience. 27 (11): 2837–45. doi:10.1523/JNEUROSCI.4121-06.2007. PMC   6672590 . PMID   17360905.
  12. ↑ Eliassi A, Nazari M, Naghdi N (March 2009). "Role of the ventromedial hypothalamic orexin-1 receptors in regulation of gastric Acid secretion in conscious rats". Journal of Neuroendocrinology. 21 (3): 177–82. doi:10.1111/j.1365-2826.2009.01824.x. PMID   19207823. S2CID   23781282.
  13. ↑ McElhinny CJ, Lewin AH, Mascarella SW, Runyon S, Brieaddy L, Carroll FI (November 2012). "Hydrolytic instability of the important orexin 1 receptor antagonist SB-334867: possible confounding effects on in vivo and in vitro studies". Bioorganic & Medicinal Chemistry Letters. 22 (21): 6661–4. doi:10.1016/j.bmcl.2012.08.109. PMID   23031594.
  14. ↑ Smart D, Haynes AC, Williams G, Arch JR (April 2002). "Orexins and the treatment of obesity". European Journal of Pharmacology. 440 (2–3): 199–212. doi:10.1016/S0014-2999(02)01429-2. PMID   12007536.
  15. ↑ Bingham MJ, Cai J, Deehan MR (September 2006). "Eating, sleeping and rewarding: orexin receptors and their antagonists". Current Opinion in Drug Discovery & Development. 9 (5): 551–9. PMID   17002215.
  16. ↑ Borgland SL, Taha SA, Sarti F, Fields HL, Bonci A (February 2006). "Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine". Neuron. 49 (4): 589–601. doi: 10.1016/j.neuron.2006.01.016 . PMID   16476667.
  17. ↑ Narita M, Nagumo Y, Hashimoto S, Narita M, Khotib J, Miyatake M, et al. (January 2006). "Direct involvement of orexinergic systems in the activation of the mesolimbic dopamine pathway and related behaviors induced by morphine". The Journal of Neuroscience. 26 (2): 398–405. doi:10.1523/JNEUROSCI.2761-05.2006. PMC   6674410 . PMID   16407535.
  18. ↑ Lawrence AJ, Cowen MS, Yang HJ, Chen F, Oldfield B (July 2006). "The orexin system regulates alcohol-seeking in rats". British Journal of Pharmacology. 148 (6): 752–9. doi:10.1038/sj.bjp.0706789. PMC   1617074 . PMID   16751790.
  19. ↑ Sharf R, Sarhan M, Dileone RJ (August 2008). "Orexin mediates the expression of precipitated morphine withdrawal and concurrent activation of the nucleus accumbens shell". Biological Psychiatry. 64 (3): 175–83. doi:10.1016/j.biopsych.2008.03.006. PMC   2529153 . PMID   18423425.
  20. ↑ Aston-Jones G, Smith RJ, Moorman DE, Richardson KA (2009). "Role of lateral hypothalamic orexin neurons in reward processing and addiction". Neuropharmacology. 56 (Suppl 1): 112–21. doi:10.1016/j.neuropharm.2008.06.060. PMC   2635332 . PMID   18655797.
  21. ↑ Martin-Fardon R, Weiss F (May 2014). "Blockade of hypocretin receptor-1 preferentially prevents cocaine seeking: comparison with natural reward seeking". NeuroReport. 25 (7): 485–8. doi:10.1097/wnr.0000000000000120. PMC   3981907 . PMID   24407199.
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