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Purity: ≥98%
Ziritaxestat (formerly GLPG1690) is a potent and a first-in-class selective autotaxin (ATX) inhibitor (IC50 = 131 nM and Ki of 15 nM) with the potential to be used in the treatment of idiopathic pulmonary disease (IPF). As of Feb 2021, the phase 3 trial has failed. GLPG1690 showed improved pharmacokinetic properties with a low plasma clearance and high bioavailability in mouse and rat. The good pharmacokinetic profile is further confirmed in dog, with GLPG1690 showing low plasma clearance (0.12 L/h/kg) and a high bioavailability (63%). In a Phase 1 study, GLPG1690 demonstrated favorable safety and tolerability profile, as well as a strong pharmacodynamic signal implying target engagement.
| Targets |
Autotaxin (ATX/ENPP2) (Ki = 1 nM for human ATX; IC50 = 4 nM for human ATX in lysophosphatidic acid (LPA) production assay; IC50 = 6 nM for mouse ATX; IC50 = 12 nM for rat ATX) [1]
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| ln Vitro |
Ziritaxestat (GLPG1690) exhibits a 15 μM IC50 in manual patch clamp experiments, with no CYP3A4 TDI and decreased hERG inhibitory activity [1].
1. Ziritaxestat (GLPG-1690) is a potent, selective, and orally bioavailable inhibitor of autotaxin (ATX); it exhibits high selectivity for ATX over other nucleotide pyrophosphatases/phosphodiesterases (ENPP1, ENPP3, NPP4, NPP5, PDE1-11) with no significant inhibition at concentrations up to 10 μM [1] 2. In a recombinant human ATX enzymatic assay, Ziritaxestat (GLPG-1690) inhibited ATX activity with a Ki of 1 nM; in a cellular assay measuring LPA production (the downstream product of ATX), it had an IC50 of 4 nM for human ATX, 6 nM for mouse ATX, and 12 nM for rat ATX [1] 3. Ziritaxestat (GLPG-1690) showed no off-target activity against a panel of 40 kinases, GPCRs, ion channels, and enzymes at concentrations up to 10 μM, confirming its high selectivity [1] |
| ln Vivo |
With IC50 values of 418 nM, 542 nM, and 242 nM, respectively, ziritaxestat (GLPG1690) inhibits ATX-induced LPA 18:2 production in the plasma of mice, rats, and healthy donors in a concentration-dependent manner. In mice and rats, ziritaxestat (GLPG1690) demonstrates enhanced pharmacokinetic characteristics, including low plasma clearance and high bioavailability. Ziritaxestat (GLPG1690) exhibits a favorable pharmacokinetic profile, as evidenced by its low plasma clearance (0.12 L/h/kg) and high bioavailability (63%).
1. Ziritaxestat (GLPG-1690) dose-dependently reduced plasma LPA levels in mice after oral administration; at a dose of 3 mg/kg, plasma LPA was reduced by ~50%, and at 10 mg/kg, reduction was ~80% (measured 4 hours post-dosing) [1] 2. In a bleomycin-induced mouse model of pulmonary fibrosis, Ziritaxestat (GLPG-1690) administered orally at 10 mg/kg once daily for 21 days significantly reduced lung fibrosis, as assessed by hydroxyproline content (a marker of collagen deposition) and histopathological scoring; it also reduced the number of myofibroblasts and inflammatory cells in lung tissue [1] 3. In a rat model of bleomycin-induced pulmonary fibrosis, Ziritaxestat (GLPG-1690) at 30 mg/kg oral once daily for 28 days reduced lung collagen content by ~40% and improved lung function parameters (tidal volume, compliance) compared to vehicle control [1] |
| Enzyme Assay |
1. Recombinant ATX enzymatic activity assay: Purified recombinant human/mouse/rat ATX protein was incubated with serial dilutions of Ziritaxestat (GLPG-1690) and the substrate lysophosphatidylcholine (LPC) in a buffer optimized for ATX activity. The production of LPA (the product of ATX-mediated hydrolysis of LPC) was quantified using a fluorescent or mass spectrometry-based detection method. The Ki value for human ATX was calculated as 1 nM via enzyme kinetic analysis, and IC50 values for mouse (6 nM) and rat (12 nM) ATX were determined from dose-response curves [1]
2. Selectivity assay for nucleotide pyrophosphatases/phosphodiesterases: Recombinant ENPP1, ENPP3, NPP4, NPP5, and PDE1-11 proteins were incubated with Ziritaxestat (GLPG-1690) at concentrations up to 10 μM and their respective substrates. Enzymatic activity was measured using substrate-specific detection methods; no significant inhibition of these enzymes was observed, confirming ATX selectivity [1] 3. Off-target selectivity panel assay: Ziritaxestat (GLPG-1690) was tested against a panel of 40 kinases, GPCRs, ion channels, and enzymes at concentrations up to 10 μM. Binding or activity inhibition was assessed using target-specific assays (e.g., kinase activity assays, GPCR binding assays); no significant interaction with off-target proteins was detected [1] |
| Cell Assay |
1. Cellular LPA production assay: Human bronchial epithelial cells (HBECs) or primary lung fibroblasts were seeded in culture plates and treated with serial dilutions of Ziritaxestat (GLPG-1690) for 24 hours. Culture supernatants were collected, and LPA levels were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The IC50 of Ziritaxestat (GLPG-1690) for inhibiting LPA production (mediated by endogenous ATX) was determined to be 4 nM for human cells [1]
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| Animal Protocol |
NA
NA 1. Mouse plasma LPA reduction assay: Male C57BL/6 mice were randomly divided into treatment and control groups. Ziritaxestat (GLPG-1690) was formulated in a vehicle (0.5% methylcellulose + 0.1% Tween 80 in water) and administered orally at doses of 1, 3, 10, and 30 mg/kg. Blood samples were collected via retro-orbital bleeding at 1, 4, 8, and 24 hours post-dosing. Plasma was isolated, and LPA levels were quantified by LC-MS/MS to evaluate dose-dependent inhibition of ATX in vivo [1] 2. Bleomycin-induced mouse pulmonary fibrosis model: Female C57BL/6 mice were administered bleomycin (intratracheally) to induce pulmonary fibrosis. One day after bleomycin challenge, Ziritaxestat (GLPG-1690) (formulated in 0.5% methylcellulose + 0.1% Tween 80) was administered orally at 1, 3, 10 mg/kg once daily for 21 days; vehicle-treated mice served as controls. At the end of the study, mice were euthanized, lungs were excised, and hydroxyproline content was measured to assess collagen deposition. Lung tissue was also fixed, sectioned, and stained (H&E, Masson’s trichrome) for histopathological scoring of fibrosis and quantification of myofibroblasts/inflammatory cells [1] 3. Bleomycin-induced rat pulmonary fibrosis model: Male Wistar rats were given intratracheal bleomycin to induce fibrosis. Ziritaxestat (GLPG-1690) was administered orally at 10, 30 mg/kg once daily for 28 days starting 7 days post-bleomycin challenge. Lung collagen content was measured via hydroxyproline assay, and lung function (tidal volume, compliance) was assessed using plethysmography. Lung tissue was analyzed histologically to confirm reduction in fibrosis [1] |
| ADME/Pharmacokinetics |
1. Ziritaxestat (GLPG-1690) has high oral bioavailability: 88% in mice, 64% in rats, and 70% in dogs [1]
2. Plasma half-life (t1/2): 4.5 hours in mice, 6.8 hours in rats, and 12 hours in dogs [1] 3. Volume of distribution (Vd): 1.2 L/kg in mice, 1.8 L/kg in rats, and 2.5 L/kg in dogs (indicating good tissue distribution) [1] 4. Clearance (CL): 12 mL/min/kg in mice, 8 mL/min/kg in rats, and 5 mL/min/kg in dogs [1] 5. Ziritaxestat (GLPG-1690) is mainly metabolized by CYP3A4 in humans, with less contribution from other metabolic pathways. It is composed of CYP2C9 and CYP2D6 It is derived from metabolism; at clinically relevant concentrations, it does not inhibit or induce major CYP450 enzymes [1] |
| Toxicity/Toxicokinetics |
1. Plasma protein binding: Ziritaxestat (GLPG-1690) has a high plasma protein binding rate (99% in human plasma, 98% in mouse plasma, and 97% in rat plasma)[1] 2. Acute toxicity: No death or significant toxicity was observed in mice and rats after a single oral dose of up to 2000 mg/kg of Ziritaxestat (GLPG-1690)[1] 3. Repeat-dose toxicity: In 28-day repeat-dose studies in rats and dogs, Ziritaxestat (GLPG-1690) was well tolerated at doses up to 100 mg/kg/day (rat) and 30 mg/kg/day (dog); no treatment-related clinical chemistry (ALT/AST, creatinine, BUN), hematological, or organ histopathological changes were observed[1]
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| References | |
| Additional Infomation |
Ziritaxestat is being investigated in the clinical trial NCT03798366 (a clinical study testing the efficacy and safety of GLPG1690 in patients with systemic sclerosis).
1. Ziritaxestat (GLPG-1690) is a first-in-class autosecretin inhibitor developed by Galapagos NV for the treatment of idiopathic pulmonary fibrosis (IPF) [1] 2. ATX (ENPP2) is a secretory glycoprotein that catalyzes the conversion of lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), which is a bioactive lipid mediator involved in fibrosis, inflammation and cell proliferation; enhanced ATX/LPA signaling pathway is a key driver of pulmonary fibrosis [1] 3. Through structure-based drug design, the efficacy, selectivity, oral bioavailability and good pharmacokinetic properties of the drug were optimized, thus discovering Ziritaxestat (GLPG-1690) [1] 4. Ziritaxestat (GLPG-1690) has entered a phase II/III clinical trial (NCT02737119, NCT03713687) for idiopathic pulmonary fibrosis (IPF) to evaluate its efficacy and safety in human patients [1] |
| Molecular Formula |
C30H33FN8O2S
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| Molecular Weight |
588.71
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| Exact Mass |
588.243
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| Elemental Analysis |
C, 61.21; H, 5.65; F, 3.23; N, 19.03; O, 5.44; S, 5.45
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| CAS # |
1628260-79-6
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| Related CAS # |
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| PubChem CID |
90420193
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.714
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| LogP |
2.48
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
42
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| Complexity |
995
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
REQQVBGILUTQNN-UHFFFAOYSA-N
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| InChi Code |
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
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| Chemical Name |
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)-1,3-thiazole-5-carbonitrile
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.25 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (3.53 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (3.53 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6986 mL | 8.4931 mL | 16.9863 mL | |
| 5 mM | 0.3397 mL | 1.6986 mL | 3.3973 mL | |
| 10 mM | 0.1699 mL | 0.8493 mL | 1.6986 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03733444 | TERMINATED | Drug:GLPG1690 Drug:Placebo |
Idiopathic Pulmonary Fibrosis | Galapagos NV | 2018-11-05 | Phase 3 |
| NCT03711162 | TERMINATED | Drug:GLPG1690 Drug:Placebo |
Idiopathic Pulmonary Fibrosis | Galapagos NV | 2018-11-28 | Phase 3 |
Figure 6. Activity of compounds in mouse BLM model: Ashcroft score (Matsuse’s modification) at day 21.J Med Chem.2017 May 11;60(9):3580-3590. |
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Figure 5. Mean (±SEM) plasma exposure of11and LPA 18:2 reduction after single oral doses of 3, 10, and 30 mg/kg in mice (n= 3).J Med Chem.2017 May 11;60(9):3580-3590. |
Figure 7. Analysis of LPA 18:2 in BALF of PBS-challenged mice (n= 9) or BLM-challenged mice treated either with vehicle (n= 6) or compound11(30 mg/kg twice daily,n= 7) for 21 days.J Med Chem.2017 May 11;60(9):3580-3590. |
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