| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
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| 5mg |
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| 10mg | |||
| Other Sizes |
| Targets |
ADAMTS-5 19 nM (IC50) ADAMTS-4 156 nM (IC50) MMP-2 1158 nM (IC50) MMP-14 >3198 nM (IC50)
ADAMTS5 (ADAM metallopeptidase with thrombospondin type 1 motif 5), also known as aggrecanase-2. ADAMTS-5 is a key enzyme responsible for the cleavage of aggrecan, a major proteoglycan component of articular cartilage. By selectively inhibiting ADAMTS-5, the drug aims to reduce cartilage degradation and slow the progression of osteoarthritis. |
|---|---|
| ln Vitro |
Not specified for standard biochemical assays; the compound is a potent and selective ADAMTS-5 inhibitor in vitro. Its anti-catabolic activity has been evaluated in murine and human cartilage explants where it demonstrated significant protective effects. Activity was confirmed using an AGC ELISA with human aggrecan.
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| ln Vivo |
In mice, rats, and dogs, GLPG1972 (oral gavage; 5 mg/kg; single dosage) showed positive pharmacokinetic characteristics. In mice, rats, and dogs, the oral availability (F%) is 25, 58%, and 97%, respectively [1].
In a preclinical mouse model of osteoarthritis (destabilization of the medial meniscus, DMM), oral administration of Aldumastat demonstrated significant protective efficacy on both articular cartilage and subchondral bone. In Phase 1b clinical trials, oral daily doses of 100-300 mg in patients with knee/hip OA showed a decrease in serum ARGS-aggrecan biomarker levels by up to 95% below baseline, indicating strong target engagement. |
| Enzyme Assay |
ADAMTS-5 inhibitory activity was confirmed in a biochemical assay using a fluorogenic peptide substrate and recombinant human ADAMTS-5. In this assay, the compound's half-maximal inhibitory concentration (IC50) was determined to be 19.0 nM. The assay utilized FAM-TBIS-1 as the fluorescent substrate. This method is a standard approach for assessing direct protease inhibition.
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| Cell Assay |
The anti-catabolic activity of GLPG1972 was evaluated using a cartilage explant assay. In this cell-based model, murine or human cartilage explants are cultured in the presence of the compound. Catabolic activity, resulting from the breakdown of aggrecan, is measured by quantifying the release of ARGS-aggrecan neoepitope fragments into the culture medium using a specific ELISA.
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| Animal Protocol |
In the destabilization of the medial meniscus (DMM) mouse model, where OA is surgically induced by transecting the medial meniscotibial ligament, the test compound was administered orally. Efficacy parameters included histomorphometric assessment of articular cartilage structure and subchondral bone plate thickness. A significant protective effect on both cartilage and bone was demonstrated with oral treatment.
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| ADME/Pharmacokinetics |
In healthy volunteers and OA patients, Aldumastat was rapidly absorbed following oral administration. In a Phase Ib study with once-daily dosing of 100, 200, or 300 mg for 29 days, the drug was absorbed and reached steady-state after about 5 days (accumulation ratio ≈1.4). It had an elimination half-life of approximately 10 hours, and a proportional increase in exposure was observed with increasing dose levels.
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| Toxicity/Toxicokinetics |
Across clinical trials, Aldumastat was generally safe and well-tolerated, with most adverse events being mild and transient. In a Phase 1 study, no serious adverse events were reported. One female participant in the 300 mg group was discontinued due to drug-related elevated liver transaminase values, which returned to normal after discontinuation without changes in bilirubin levels. No overall trends in laboratory abnormalities, vital signs, or ECG parameters were observed.
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| References | |
| Additional Infomation |
Aldumastat has completed Phase 2 clinical trials for knee osteoarthritis (e.g., the ROCCELLA trial). The primary objective of the Phase 2 study was to evaluate the effect on medial femorotibial compartment cartilage thickness over 52 weeks. Although the primary endpoint was not met, the compound demonstrated a good safety profile and was generally well-tolerated. The development of Aldumastat for OA has been discontinued following these Phase 2 results.
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| Molecular Formula |
C20H24F2N4O3
|
|---|---|
| Molecular Weight |
406.426371574402
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| Exact Mass |
406.181
|
| CAS # |
1957278-93-1
|
| PubChem CID |
121448788
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| Appearance |
White to off-white solid powder
|
| LogP |
1.6
|
| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
6
|
| Rotatable Bond Count |
5
|
| Heavy Atom Count |
29
|
| Complexity |
679
|
| Defined Atom Stereocenter Count |
2
|
| SMILES |
FC1C=C(C=C(C=1)N1CCN(C[C@@H]1C)C(CC[C@@]1(C(NC(N1)=O)=O)C1CC1)=O)F
|
| InChi Key |
CMLVKUWQFZQPPS-YUNKPMOVSA-N
|
| InChi Code |
InChI=1S/C20H24F2N4O3/c1-12-11-25(6-7-26(12)16-9-14(21)8-15(22)10-16)17(27)4-5-20(13-2-3-13)18(28)23-19(29)24-20/h8-10,12-13H,2-7,11H2,1H3,(H2,23,24,28,29)/t12-,20-/m0/s1
|
| Chemical Name |
(5S)-5-cyclopropyl-5-[3-[(3S)-4-(3,5-difluorophenyl)-3-methylpiperazin-1-yl]-3-oxopropyl]imidazolidine-2,4-dione
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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 |
| 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) |
DMSO: 100 mg/mL (246.04 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5 mg/mL (12.30 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 50.0 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. Solubility in Formulation 2: ≥ 5 mg/mL (12.30 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 50.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 5 mg/mL (12.30 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 | 2.4604 mL | 12.3022 mL | 24.6045 mL | |
| 5 mM | 0.4921 mL | 2.4604 mL | 4.9209 mL | |
| 10 mM | 0.2460 mL | 1.2302 mL | 2.4604 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.
Link: https://clinicaltrials.gov/ct2/show/NCT03595618
Conditions:OsteoarthritisLink: https://clinicaltrials.gov/ct2/show/NCT04136327
Conditions:HealthyLink: https://clinicaltrials.gov/ct2/show/NCT03143725
Conditions:HealthyProducts are for research use only; We do not sell to patients
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