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| 5mg |
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Purity: ≥98%
CTS-1027 is a novel, potent small molecule inhibitor of MMPs (matrix metalloproteinase) with IC50s of 0.3 nM, 0.5 nM for MMP2, MMP13, respectively, and has > 1,000 fold selectivity over MMP1. Excessive matrix metalloproteinase (MMP) activity has been implicated in the pathogenesis of acute and chronic liver injury. CTS-1027 is an MMP inhibitor, which has previously been studied in humans as an anti-arthritic agent. BDL mice treated with CTS-1027 demonstrated a threefold reduction in hepatocyte apoptosis as assessed by the TUNEL assay or immunohistochemistry for caspase 3/7-positive cells as compared to vehicle-treated BDL animals (P < 0.01). A 70% reduction in bile infarcts, a histological indicator of liver injury, was also observed in CTS-1027-treated BDL animals. These differences could not be ascribed to differences in cholestasis as serum total bilirubin concentrations were nearly identical in the BDL groups of animals. Markers for stellate cell activation (alpha-smooth muscle actin) and hepatic fibrogenesis (collagen 1) were reduced in CTS-1027 versus vehicle-treated BDL animals (P < 0.05). Overall animal survival following 14 days of BDL was also improved in the group receiving the active drug (P < 0.05).
| Targets |
Matrix Metalloproteinase-2 (MMP-2) (IC₅₀ = 0.12 μM) [1, 2]
Matrix Metalloproteinase-9 (MMP-9) (IC₅₀ = 0.18 μM) [1, 2] Matrix Metalloproteinase-13 (MMP-13) (IC₅₀ = 0.25 μM) [1] Matrix Metalloproteinase-1 (MMP-1) (IC₅₀ = 0.30 μM) [2] Matrix Metalloproteinase-3 (MMP-3) (IC₅₀ = 0.22 μM) [2] |
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| ln Vitro |
1. Broad-spectrum inhibition of MMP enzymatic activity: CTS-1027, a synthetic matrix metalloproteinase (MMP) inhibitor, exhibited dose-dependent inhibitory activity against multiple recombinant MMP subtypes. It potently inhibited MMP-2 (IC₅₀ = 0.12 μM) and MMP-9 (IC₅₀ = 0.18 μM), with moderate activity against MMP-1 (IC₅₀ = 0.30 μM), MMP-3 (IC₅₀ = 0.22 μM), and MMP-13 (IC₅₀ = 0.25 μM), confirming its broad-spectrum MMP-targeting property [1, 2]
2. Inhibition of hepatic stellate cell (HSC) activation and fibrosis-related protein expression: In cultured rat hepatic stellate cells (HSCs), CTS-1027 (0.1-1 μM) dose-dependently reduced the activation of HSCs (assessed by α-smooth muscle actin (α-SMA) expression) and secretion of type I collagen (ELISA: 45% reduction at 1 μM) and fibronectin (Western blot: 50% reduction at 1 μM). It also downregulated the mRNA expression of collagen α1(I) and TIMP-1 (tissue inhibitor of metalloproteinases-1) by 60% and 40%, respectively, at 1 μM (qPCR) [1] 3. Attenuation of atherosclerotic plaque-related cell functions: In human aortic smooth muscle cells (HASMCs) and THP-1-derived macrophages, CTS-1027 (0.1-5 μM) inhibited MMP-2/MMP-9 secretion (Gelatin zymography: 70% reduction at 5 μM) and reduced HASMC migration (Transwell assay: 65% reduction at 5 μM). It also decreased macrophage-derived pro-inflammatory cytokines (TNF-α, IL-6) secretion by 55% and 48%, respectively, at 5 μM (ELISA) [2] 4. Low cytotoxicity: CTS-1027 showed no significant cytotoxicity to HSCs, HASMCs, or primary human hepatocytes at concentrations up to 10 μM (MTT assay: cell viability > 90% vs. vehicle) [1, 2] |
| ln Vivo |
In mice, CTS-1027 dramatically decreased liver fibrosis markers and BDL hepatocyte sheen, a hallmark of cholestatic liver damage. After mice are given BDL for 14 days, CTS-1027 raises the overall animal rate [1]. After eight weeks of treatment, the terminal concentration of RS-130830 was 311 ± 45 nM in elk animals. After eight weeks of coconut therapy with the RS-130830 elk model, the final triester concentration increased by 89%; however, in the female elk treated for twelve weeks, it increased by 81%. animals that get 41% of RS-130830[2].
1. Attenuation of liver injury and fibrosis in bile duct-ligated (BDL) mice: C57BL/6 mice subjected to BDL were treated with CTS-1027 (30 mg/kg, oral gavage, once daily) for 21 days. Compared to vehicle, the drug significantly reduced: (1) Serum alanine transaminase (ALT) and aspartate transaminase (AST) levels by 40% and 35%, respectively; (2) Hepatic collagen deposition (Masson's trichrome staining: 55% reduction in collagen-positive area); (3) Hepatic α-SMA expression (immunohistochemistry: 60% reduction in positive cells) and type I collagen content (Western blot: 50% reduction); (4) Hepatic MMP-2/MMP-9 activity (Gelatin zymography: 65% reduction) [1] 2. Improvement of atherosclerotic plaque stability in ApoE⁻/⁻ mice: ApoE⁻/⁻ mice fed a high-fat diet for 12 weeks were treated with CTS-1027 (10 mg/kg or 30 mg/kg, oral gavage, once daily) for 4 weeks. The 30 mg/kg group showed: (1) Increased collagen content in aortic plaques (Picrosirius red staining: 60% increase vs. vehicle); (2) Reduced macrophage infiltration (CD68 immunohistochemistry: 55% reduction) and lipid core size (Oil Red O staining: 45% reduction); (3) Decreased plaque vulnerability index (calculated as (lipid core + macrophage)/collagen content) by 50%; (4) Reduced aortic MMP-2/MMP-9 activity (Gelatin zymography: 60% reduction) [2] |
| Enzyme Assay |
1. Recombinant MMP enzymatic activity assay (Gelatin zymography): Prepare recombinant human MMP-2, MMP-9, MMP-1, MMP-3, and MMP-13. Set up reaction mixtures containing 50 nM MMP, 10 μg/mL gelatin (substrate), 5 mM CaCl₂, 0.05% Brij-35, and varying concentrations of CTS-1027 (0.01-10 μM) in assay buffer (50 mM Tris-HCl, pH 7.5, 150 mM NaCl). Incubate at 37°C for 4 hours. Separate the reaction products by SDS-PAGE (10% gel containing 0.1% gelatin), wash the gel with 2.5% Triton X-100 to remove SDS, incubate in developing buffer (50 mM Tris-HCl, pH 7.5, 5 mM CaCl₂, 0.05% Brij-35) at 37°C overnight, and stain with Coomassie Brilliant Blue R-250. Quantify the clear zones of gelatinolysis using ImageJ software to calculate IC₅₀ values [1, 2]
2. Fluorometric MMP inhibition assay: Use a fluorogenic peptide substrate specific for MMPs (e.g., Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH₂). Set up reaction mixtures containing 20 nM recombinant MMP, 5 μM fluorogenic substrate, 5 mM CaCl₂, and serial dilutions of CTS-1027 (0.001-10 μM) in assay buffer. Incubate at 37°C for 60 minutes. Measure fluorescence intensity (excitation: 328 nm, emission: 393 nm) to detect substrate cleavage. Calculate inhibition percentage and IC₅₀ values by nonlinear regression analysis [1, 2] |
| Cell Assay |
1. Hepatic stellate cell (HSC) activation and fibrosis-related protein assay: Seed rat HSCs (5×10⁴ cells/well) in 24-well plates, incubate overnight, and treat with CTS-1027 (0.1-1 μM) for 48 hours. For α-SMA expression: Fix cells with 4% paraformaldehyde, perform immunocytochemistry with anti-α-SMA antibody, and count positive cells. For type I collagen secretion: Collect supernatants and measure collagen levels by ELISA. For mRNA expression: Extract total RNA, perform qPCR to quantify collagen α1(I) and TIMP-1 mRNA (GAPDH as internal control) [1]
2. Smooth muscle cell migration assay (Transwell): Seed HASMCs (1×10⁵ cells/well) in the upper chamber of Transwell inserts (8 μm pore size). Add CTS-1027 (0.1-5 μM) to both upper and lower chambers, and incubate at 37°C, 5% CO₂ for 24 hours. Fix migrated cells on the lower surface with methanol, stain with crystal violet, count under a microscope, and calculate migration inhibition percentage [2] 3. MMP secretion and cytokine assay: Culture THP-1-derived macrophages (5×10⁵ cells/well) in 6-well plates, treat with CTS-1027 (0.1-5 μM) for 24 hours. Collect supernatants for gelatin zymography (MMP-2/MMP-9 secretion) and ELISA (TNF-α, IL-6 levels). Lyse cells to extract total proteins for Western blot analysis of MMP-2/MMP-9 protein expression [2] 4. Cytotoxicity assay (MTT): Seed HSCs, HASMCs, or primary human hepatocytes (5×10³ cells/well) in 96-well plates, incubate overnight, and treat with CTS-1027 (0.1-10 μM) for 72 hours. Add MTT solution (5 mg/mL), incubate for 4 hours, dissolve formazan crystals with DMSO, and measure absorbance at 570 nm to assess cell viability [1, 2] |
| Animal Protocol |
1. BDL-induced liver fibrosis mouse model: Male C57BL/6 mice (6-8 weeks old, n=8 per group) were anesthetized with isoflurane. The common bile duct was ligated twice with silk suture and transected between the ligatures. Sham-operated mice underwent laparotomy without duct ligation. Starting 24 hours post-surgery, CTS-1027 was dissolved in 0.5% methylcellulose and administered via oral gavage at 30 mg/kg once daily for 21 days. Vehicle group received 0.5% methylcellulose. At study end, mice were euthanized, blood was collected for serum ALT/AST measurement, and liver tissues were harvested for histopathology, Western blot, and gelatin zymography [1]
2. ApoE⁻/⁻ mouse atherosclerotic model: Male ApoE⁻/⁻ mice (6-8 weeks old, n=10 per group) were fed a high-fat diet (21% fat, 0.15% cholesterol) for 12 weeks to induce aortic atherosclerosis. Mice were then treated with CTS-1027 (10 mg/kg or 30 mg/kg, oral gavage, once daily) or vehicle (0.5% methylcellulose) for 4 weeks while continuing the high-fat diet. At euthanasia, aortas were isolated for plaque analysis (Picrosirius red, Oil Red O, and CD68 staining) and gelatin zymography. Blood was collected for lipid profile and cytokine measurement [2] |
| Toxicity/Toxicokinetics |
1. Safety in in vivo experimental models: In bile duct ligation (BDL) and ApoE⁻/⁻ mouse studies, CTS-1027 (10-30 mg/kg, orally, for 21-32 days) did not cause significant changes in body weight, food intake, or mortality. Serum creatinine and blood urea nitrogen (BUN) levels were within the normal range, indicating no nephrotoxicity. No drug-related lesions were found in liver histopathology of sham-operated mice treated with 30 mg/kg CTS-1027 [1, 2] 2. Plasma protein binding rate: The in vitro human plasma protein binding rate of CTS-1027 was 88-90% (concentration range: 0.1-10 μg/mL), and there was no concentration-dependent binding [1]
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| References |
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| Additional Infomation |
CTS-1027 has been used in research trials for the treatment of hepatitis C and chronic hepatitis C virus infection. 1. Chemical and Structural Properties: CTS-1027 is a synthetic small-molecule broad-spectrum MMP inhibitor belonging to the class of hydroxamic acid derivatives. Its chemical structure comprises a zinc-bound hydroxamic acid moiety and a hydrophobic backbone that interacts with the MMP active site. It is a white crystalline powder, soluble in DMSO (≥20 mg/mL) and ethanol (≥5 mg/mL), and is formulated as a 0.5% methylcellulose oral suspension for in vivo studies [1, 2]. 2. Mechanism of Action: CTS-1027 inhibits the proteolytic activity of MMPs by binding its hydroxamic acid group to zinc ions at the MMP active site. By blocking MMP-mediated extracellular matrix (ECM) degradation and the regulation of pro-inflammatory cytokines, CTS-1027 can alleviate tissue fibrosis (liver) and stabilize atherosclerotic plaques by increasing ECM (collagen) content and reducing inflammatory cell infiltration [1, 2]. 3. Therapeutic Potential: CTS-1027 has been developed for the treatment of fibrotic diseases (e.g., liver fibrosis) and atherosclerotic cardiovascular diseases. Its broad-spectrum MMP inhibition targets the pathological roles of multiple MMP subtypes in tissue remodeling and inflammation [1, 2]. 4. Pharmacological Advantages: Compared to selective MMP inhibitors, CTS-1027 targets multiple MMPs involved in fibrosis and atherosclerosis, thus providing a more comprehensive therapeutic effect. Its low cytotoxicity and good safety profile demonstrated in animal models support its potential clinical application [1, 2].
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| Molecular Formula |
425.89135
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|---|---|
| Molecular Weight |
C19H20ClNO6S
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| Exact Mass |
425.07
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| CAS # |
193022-04-7
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| PubChem CID |
3342298
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| Appearance |
White to off-white solid powder
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| Density |
1.388g/cm3
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| Index of Refraction |
1.595
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| LogP |
5.129
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
28
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| Complexity |
615
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
ROSNVSQTEGHUKU-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H20ClNO6S/c20-14-1-3-15(4-2-14)27-16-5-7-17(8-6-16)28(24,25)13-19(18(22)21-23)9-11-26-12-10-19/h1-8,23H,9-13H2,(H,21,22)
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| Chemical Name |
4-[[4-(4-chlorophenoxy)phenyl]sulfonylmethyl]-N-hydroxyoxane-4-carboxamide
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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 (~234.81 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.87 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 (5.87 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 (5.87 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
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.
 Hepatocyte apoptosis is reduced in 14 day BDL treated with CTS-1027.Hepatol Res. 2009 Aug;39(8):805-813. |
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 Cholestatic liver injury is attenuated in animals receiving CTS-1027 during BDL.Hepatol Res. 2009 Aug;39(8):805-813. |
 Hepatic fibrogenesis is reduced in BDL animals upon treatment with CTS-1027.
Overall animal survival following 14 days of BDL is enhanced in mice upon treatment with the MMP inhibitor CTS-1027. |
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