GSK1521498   Click here for help

GtoPdb Ligand ID: 9287

Synonyms: GSK-1521498
Compound class: Synthetic organic
Comment: GSK1521498 is a μ opioid receptor antagonist [4-5] in clinical development for disorders of compulsive consumption (e.g stimulant drug seeking, binge eating [7], or excessive alcohol consumption). It is >10-fold selective for human μ receptor compared to the κ and δ receptors in vitro [4]. It may be used experimentally as the phosphate with IUPAC name N-{[3,5-difluoro-3′-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine phosphate (1:1). The chemical structure of GSK1521498 is claimed in patent US8822518 [2], with prior chemical series claimed in WO2008021849 [1].
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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View interactive charts of activity data across species
2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 3
Hydrogen bond donors 2
Rotatable bonds 5
Topological polar surface area 53.6
Molecular weight 402.17
XLogP 5.41
No. Lipinski's rules broken 1
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

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Canonical SMILES Fc1cc(cc(c1CNC1Cc2c(C1)cccc2)F)c1cccc(c1)c1ncn[nH]1
Isomeric SMILES Fc1cc(cc(c1CNC1Cc2c(C1)cccc2)F)c1cccc(c1)c1ncn[nH]1
InChI InChI=1S/C24H20F2N4/c25-22-11-19(15-6-3-7-18(8-15)24-28-14-29-30-24)12-23(26)21(22)13-27-20-9-16-4-1-2-5-17(16)10-20/h1-8,11-12,14,20,27H,9-10,13H2,(H,28,29,30)
InChI Key WIEDUMBCZQRGSY-UHFFFAOYSA-N
References
1. Cowan DJ, Larkin AL, Zhang C, Musso DL, Green GM, Cadilla R, Spearing PK, Bishop MJ, Speake JD. (2008)
Novel compounds as antagonists or inverse agonists at opioid receptors.
Patent number: WO2008021849. Assignee: Smithkline Beecham Corporation. Priority date: 09/08/2006. Publication date: 21/02/2008.
2. Cowan DJ, Larkin AL, Zhang C, Musso DL, Green GM, Cadilla R, Spearing PK, Bishop MJ, Speake JD. (2014)
Compounds as antagonists or inverse agonists of opioid receptors for treatment of addiction.
Patent number: US8822518. Assignee: Glaxosmithkline Llc. Priority date: 09/08/2006. Publication date: 02/09/2014.
3. Giuliano C, Goodlett CR, Economidou D, García-Pardo MP, Belin D, Robbins TW, Bullmore ET, Everitt BJ. (2015)
The Novel μ-Opioid Receptor Antagonist GSK1521498 Decreases Both Alcohol Seeking and Drinking: Evidence from a New Preclinical Model of Alcohol Seeking.
Neuropsychopharmacology, 40 (13): 2981-92. [PMID:26044906]
4. Ignar DM, Goetz AS, Noble KN, Carballo LH, Stroup AE, Fisher JC, Boucheron JA, Brainard TA, Larkin AL, Epperly AH et al.. (2011)
Regulation of ingestive behaviors in the rat by GSK1521498, a novel micro-opioid receptor-selective inverse agonist.
J Pharmacol Exp Ther, 339 (1): 24-34. [PMID:21712426]
5. Kelly E, Mundell SJ, Sava A, Roth AL, Felici A, Maltby K, Nathan PJ, Bullmore ET, Henderson G. (2015)
The opioid receptor pharmacology of GSK1521498 compared to other ligands with differential effects on compulsive reward-related behaviours.
Psychopharmacology (Berl.), 232 (1): 305-14. [PMID:24973897]
6. Nathan PJ, Bush MA, Tao WX, Koch A, Davies KM, Maltby K, O'Neill BV, Napolitano A, Skeggs AL, Brooke AC et al.. (2012)
Multiple-dose safety, pharmacokinetics, and pharmacodynamics of the μ-opioid receptor inverse agonist GSK1521498.
J Clin Pharmacol, 52 (10): 1456-67. [PMID:22162534]
7. Nathan PJ, O'Neill BV, Bush MA, Koch A, Tao WX, Maltby K, Napolitano A, Brooke AC, Skeggs AL, Herman CS et al.. (2012)
Opioid receptor modulation of hedonic taste preference and food intake: a single-dose safety, pharmacokinetic, and pharmacodynamic investigation with GSK1521498, a novel μ-opioid receptor inverse agonist.
J Clin Pharmacol, 52 (4): 464-74. [PMID:21610207]
8. Rabiner EA, Beaver J, Makwana A, Searle G, Long C, Nathan PJ, Newbould RD, Howard J, Miller SR, Bush MA et al.. (2011)
Pharmacological differentiation of opioid receptor antagonists by molecular and functional imaging of target occupancy and food reward-related brain activation in humans.
Mol Psychiatry, 16 (8): 826-35, 785. [PMID:21502953]
9. Ripley TL, Sanchez-Roige S, Bullmore ET, Mugnaini M, Maltby K, Miller SR, Wille DR, Nathan P, Stephens DN. (2015)
The novel mu-opioid antagonist, GSK1521498, reduces ethanol consumption in C57BL/6J mice.
Psychopharmacology (Berl.), 232 (18): 3431-41. [PMID:26141191]
10. Ziauddeen H, Chamberlain SR, Nathan PJ, Koch A, Maltby K, Bush M, Tao WX, Napolitano A, Skeggs AL, Brooke AC et al.. (2013)
Effects of the mu-opioid receptor antagonist GSK1521498 on hedonic and consummatory eating behaviour: a proof of mechanism study in binge-eating obese subjects.
Mol Psychiatry, 18 (12): 1287-93. [PMID:23147384]
11. Ziauddeen H, Nestor LJ, Subramaniam N, Dodds C, Nathan PJ, Miller SR, Sarai BK, Maltby K, Fernando D, Warren L et al.. (2016)
Opioid Antagonists and the A118G Polymorphism in the μ-Opioid Receptor Gene: Effects of GSK1521498 and Naltrexone in Healthy Drinkers Stratified by OPRM1 Genotype.
Neuropsychopharmacology, 41 (11): 2647-57. [PMID:27109624]