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| Targets |
Cipemastat targets matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases that play crucial roles in the degradation of extracellular matrix (ECM) proteins. The compound is selective for collagenase 1 (MMP-1), collagenase 2 (MMP-8), and collagenase 3 (MMP-13) relative to other MMPs. Cipemastat also inhibits gelatinase B (MMP-9). By inhibiting MMPs, Cipemastat prevents the breakdown of ECM components such as collagen, which is important in tissue remodeling, inflammation, and cancer metastasis.
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| ln Vitro |
Human matrix metalloproteinases are effectively and competitively inhibited by cipemastat (Ro 32-3555). Comparing Cipemastat to comparable matrix metalloproteinases, it is selective for collagenase 1, 2, and 3. Additionally, rat collagenase exhibits strong inhibition from dipemastat (IC50=44.7±3.4 nM (n=4)). cartilage degradation +/- did not act cytotoxically on explant chondrocytes; rather, it reduced IL-1a-induced cartilage degradation in vitro in a concentration-dependent manner with an IC50=60 nM. Compared to explants cultivated in the presence of IL-La alone, cipemastat fails to alter glucose consumption at any of the tested concentrations[1].
In vitro, Cipemastat effectively and competitively inhibits human matrix metalloproteinases. The compound is selective for collagenase 1 (MMP-1), collagenase 2 (MMP-8), and collagenase 3 (MMP-13) relative to other matrix metalloproteinases. Cipemastat also inhibits gelatinase B (MMP-9). Its in vitro potency and selectivity have been well characterized in enzymatic assays using purified recombinant MMPs. The compound's ability to inhibit MMPs makes it a valuable tool for studying the role of these enzymes in various physiological and pathological processes. |
| ln Vivo |
Over the course of fourteen days, the amount of hydroxyproline in cartilage implanted in animals given a vehicle dose drops to 53.6±7.1 nM/mg from 119.3±4.2 nM/mg in non-implanted cartilage. Oral Cipemastat doses of 2.5, 5, 10, and 25 mg/kg resulted in statistically higher levels of implanted cartilage hydroxyproline in the animals. The lateral femoral condyle, which is the area under analysis, is the cartilage region most frequently damaged by pannus 14 days following the second challenge injection of P. acnes. The average cartilage area in non-arthritic animals is 0.17±0.02 mm2 (n=5). There is a considerable drop to a mean area of 0.086±0.01 mm2 (n=10) in animals with arthritis. With a mean value of 0.126±0.012 mm2 (n=9), the group of mice dosed with Cipemastat (50 mg/kg, po) exhibits a considerably larger cartilage area. Animals given a vehicle dose had a pannus area of 0.099±0.017 mm2, while those given cipemastat have a pannus area of 0.102±0.019 mm2. Rats given a vehicle dosage experienced two stages of paw edema following adjuvant arthritis injection. The initial phase of swelling happened from day 0 to day 5, increasing the volume of the paws by 1.9±0.1 mL; the second phase took place from day 9 to day 14, increasing the volume of the paws by 0.98±0.08 mL. The rats administered with 0.1 mg/kg of dexamethasone exhibit a noteworthy decrease in main (0.2±0.03 mL) and secondary (0.07±0.08 mL) inflammation, paw swelling, and overall lesion score inhibition[1].
In vivo, Cipemastat has been studied extensively for its role in cancer treatment and rheumatoid arthritis. Several clinical trials have been conducted to evaluate its efficacy in these indications. As an orally active MMP inhibitor, Cipemastat was developed for the treatment of rheumatoid arthritis and was in Phase 3 clinical trials. The compound's ability to inhibit collagenases and gelatinase B suggests potential applications in diseases characterized by excessive ECM degradation. Cipemastat was approved for use in 2000 for rheumatoid arthritis. |
| Enzyme Assay |
Enzyme activity assays for Cipemastat are performed using purified recombinant human MMPs, including MMP-1, MMP-8, MMP-13, and MMP-9. Enzyme activity is measured using fluorogenic or colorimetric peptide substrates that are cleaved by MMPs. Cipemastat is incubated with the enzyme and substrate at varying concentrations in appropriate assay buffer at 37degC for a defined period. The reaction is stopped, and product formation is quantified using a fluorescence or absorbance plate reader. IC50 values are calculated from concentration-response curves.
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| Cell Assay |
Cellular assays for Cipemastat are performed using cell lines that express MMPs, such as cancer cell lines or fibroblasts. Cells are cultured in appropriate media and treated with Cipemastat at varying concentrations for defined time periods. MMP activity in conditioned media or cell lysates is measured using fluorogenic or colorimetric substrates. Cell viability and proliferation are assessed using standard assays such as MTT or CellTiter-Glo. Cell invasion and migration are assessed using Boyden chamber or wound healing assays.
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| Animal Protocol |
In vivo studies with Cipemastat were conducted in animal models of rheumatoid arthritis and cancer. The compound was administered via oral routes at defined doses and schedules. For arthritis models, joint inflammation and destruction were assessed by clinical scoring, histology, and radiographic analysis. For cancer models, tumor growth and metastasis were monitored. Cipemastat was evaluated in clinical trials for rheumatoid arthritis and cancer.
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| ADME/Pharmacokinetics |
Cipemastat has a molecular weight of 436.55 and a molecular formula of C22H36N4O5. The compound is orally active. Cipemastat was in Phase 3 clinical trials for rheumatoid arthritis and was approved for use in 2000. Detailed pharmacokinetic parameters, including oral bioavailability, half-life, and clearance, have been characterized in clinical studies. The compound has a Topological Polar Surface Area of 1.6 and a logP of 1.6.
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| Toxicity/Toxicokinetics |
Cipemastat was evaluated in clinical trials for safety and efficacy in rheumatoid arthritis and cancer. The compound was in Phase 3 clinical trials for rheumatoid arthritis and was approved for use in 2000. Common side effects associated with MMP inhibitors include musculoskeletal pain and joint stiffness. The compound's safety profile has been characterized in clinical studies. Cipemastat is for research use only and is not currently marketed for clinical use.
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| References | |
| Additional Infomation |
Cipemastat (Ro 32-3555, Trocade) is a potent, competitive, and orally active inhibitor of human matrix metalloproteinases. It is selective for collagenase 1 (MMP-1), collagenase 2 (MMP-8), and collagenase 3 (MMP-13) relative to other MMPs, and also inhibits gelatinase B (MMP-9). Cipemastat was studied extensively for its role in cancer treatment and rheumatoid arthritis, with several clinical trials conducted. It was approved for use in 2000 for rheumatoid arthritis.
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| Molecular Formula |
C₂₂H₃₆N₄O₅
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| Molecular Weight |
436.55
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| Exact Mass |
436.268
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| CAS # |
190648-49-8
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| PubChem CID |
9824350
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| Appearance |
Off-white to light yellow solid powder
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| Density |
1.2±0.1 g/cm3
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| Index of Refraction |
1.541
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| LogP |
1.38
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
31
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| Complexity |
713
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| Defined Atom Stereocenter Count |
2
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| SMILES |
CC1(C(=O)N(C(=O)N1C)C[C@@H]([C@@H](CC2CCCC2)C(=O)N3CCCCC3)C(=O)NO)C
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| InChi Key |
GFUITADOEPNRML-SJORKVTESA-N
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| InChi Code |
InChI=1S/C22H36N4O5/c1-22(2)20(29)26(21(30)24(22)3)14-17(18(27)23-31)16(13-15-9-5-6-10-15)19(28)25-11-7-4-8-12-25/h15-17,31H,4-14H2,1-3H3,(H,23,27)/t16-,17+/m1/s1
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| Chemical Name |
(2R,3R)-3-(cyclopentylmethyl)-N-hydroxy-4-oxo-4-(piperidin-1-yl)-2-((3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)methyl)butanamide
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| Synonyms |
Ro 32-3555 Cipemastat Ro32-3555 Ro-32 3555 Ro-323555
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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 (~229.07 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.73 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 25.0 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: ≥ 2.5 mg/mL (5.73 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 25.0 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: ≥ 2.5 mg/mL (5.73 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 | 2.2907 mL | 11.4534 mL | 22.9069 mL | |
| 5 mM | 0.4581 mL | 2.2907 mL | 4.5814 mL | |
| 10 mM | 0.2291 mL | 1.1453 mL | 2.2907 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.
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