ziritaxestat   Click here for help

GtoPdb Ligand ID: 9561

Synonyms: compound 11 [PMID: 28414242] | GLPG-1690 | GLPG1690
PDB Ligand Immunopharmacology Ligand
Compound class: Synthetic organic
Comment: Ziritaxestat (GLPG1690) is a selective autotaxin Inhibitor [3], that was investigated for anti-fibrotic efficacy. Animal studies using GLPG1690 suggested potential for autotaxin inhibition in breast cancer treatment [2,9] and TSC2-loss associated oncogenicity (in tuberous sclerosis complex) [4]. In early 2021 data from the phase 3 ziritaxestat program in idiopathic pulmonary fibrosis (IPF; ISABELA) was analysed, and the conclusion reached was that ziritaxestat's benefit-risk profile did not support continuing the program. At that time the decision was made to discontinue the inhibitor's phase 2 trial in systemic sclerosis.
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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 9
Hydrogen bond donors 1
Rotatable bonds 8
Topological polar surface area 132.48
Molecular weight 588.24
XLogP 3.62
No. Lipinski's rules broken 0
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 CCc1nc2n(c1N(c1sc(c(n1)c1ccc(cc1)F)C#N)C)cc(cc2C)N1CCN(CC1)CC(=O)N1CC(C1)O
Isomeric SMILES CCc1nc2n(c1N(c1sc(c(n1)c1ccc(cc1)F)C#N)C)cc(cc2C)N1CCN(CC1)CC(=O)N1CC(C1)O
InChI InChI=1S/C30H33FN8O2S/c1-4-24-29(35(3)30-34-27(25(14-32)42-30)20-5-7-21(31)8-6-20)39-15-22(13-19(2)28(39)33-24)37-11-9-36(10-12-37)18-26(41)38-16-23(40)17-38/h5-8,13,15,23,40H,4,9-12,16-18H2,1-3H3
InChI Key REQQVBGILUTQNN-UHFFFAOYSA-N
References
1. Bain G, Shannon KE, Huang F, Darlington J, Goulet L, Prodanovich P, Ma GL, Santini AM, Stein AJ, Lonergan D et al.. (2017)
Selective Inhibition of Autotaxin Is Efficacious in Mouse Models of Liver Fibrosis.
J Pharmacol Exp Ther, 360 (1): 1-13. [PMID:27754931]
2. Benesch MGK, Tang X, Brindley DN. (2020)
Autotaxin and Breast Cancer: Towards Overcoming Treatment Barriers and Sequelae.
Cancers (Basel), 12 (2). [PMID:32041123]
3. Desroy N, Housseman C, Bock X, Joncour A, Bienvenu N, Cherel L, Labeguere V, Rondet E, Peixoto C, Grassot JM et al.. (2017)
Discovery of 2-[[2-Ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methylimidazo[1,2-a]pyridin-3-yl]methylamino]-4-(4-fluorophenyl)thiazole-5-carbonitrile (GLPG1690), a First-in-Class Autotaxin Inhibitor Undergoing Clinical Evaluation for the Treatment of Idiopathic Pulmonary Fibrosis.
J Med Chem, 60 (9): 3580-3590. [PMID:28414242]
4. Feng Y, Mischler WJ, Gurung AC, Kavanagh TR, Androsov G, Sadow PM, Herbert ZT, Priolo C. (2020)
Therapeutic Targeting of the Secreted Lysophospholipase D Autotaxin Suppresses Tuberous Sclerosis Complex-Associated Tumorigenesis.
Cancer Res, 80 (13): 2751-2763. [PMID:32393662]
5. Maher TM, Kreuter M, Lederer DJ, Brown KK, Wuyts W, Verbruggen N, Stutvoet S, Fieuw A, Ford P, Abi-Saab W et al.. (2019)
Rationale, design and objectives of two phase III, randomised, placebo-controlled studies of GLPG1690, a novel autotaxin inhibitor, in idiopathic pulmonary fibrosis (ISABELA 1 and 2).
BMJ Open Respir Res, 6 (1): e000422. [PMID:31179008]
6. Maher TM, van der Aar EM, Van de Steen O, Allamassey L, Desrivot J, Dupont S, Fagard L, Ford P, Fieuw A, Wuyts W. (2018)
Safety, tolerability, pharmacokinetics, and pharmacodynamics of GLPG1690, a novel autotaxin inhibitor, to treat idiopathic pulmonary fibrosis (FLORA): a phase 2a randomised placebo-controlled trial.
Lancet Respir Med, 6 (8): 627-635. [PMID:29792287]
7. Orosa B, García S, Conde C. (2015)
The autotaxin-lysophosphatidic acid pathway in pathogenesis of rheumatoid arthritis.
Eur J Pharmacol, 765: 228-33. [PMID:26297977]
8. Park GY, Lee YG, Berdyshev E, Nyenhuis S, Du J, Fu P, Gorshkova IA, Li Y, Chung S, Karpurapu M et al.. (2013)
Autotaxin production of lysophosphatidic acid mediates allergic asthmatic inflammation.
Am J Respir Crit Care Med, 188 (8): 928-40. [PMID:24050723]
9. Tang X, Wuest M, Benesch MGK, Dufour J, Zhao Y, Curtis JM, Monjardet A, Heckmann B, Murray D, Wuest F et al.. (2020)
Inhibition of Autotaxin with GLPG1690 Increases the Efficacy of Radiotherapy and Chemotherapy in a Mouse Model of Breast Cancer.
Mol Cancer Ther, 19 (1): 63-74. [PMID:31548293]
10. van der Aar E, Desrivot J, Dupont S, Heckmann B, Fieuw A, Stutvoet S, Fagard L, Van de Wal K, Helmer E. (2019)
Safety, Pharmacokinetics, and Pharmacodynamics of the Autotaxin Inhibitor GLPG1690 in Healthy Subjects: Phase 1 Randomized Trials.
J Clin Pharmacol, 59 (10): 1366-1378. [PMID:31012984]
11. Zhao Y, Natarajan V. (2013)
Lysophosphatidic acid (LPA) and its receptors: role in airway inflammation and remodeling.
Biochim Biophys Acta, 1831 (1): 86-92. [PMID:22809994]