Marimastat
Marimastat is a broad range inhibitor of Matrix metalloproteinases with IC50 values of 5, 6, 13, 3 and 9 nM for MMP-1, MMP-2, MMP-7 , MMP-9 and MMP-14 [1].
Marimastat is an orally bioavailable inhibitor with an absolute bioavailability of 20%–50% in preclinical studies, which can bind covalently to the zinc atom of the MMP-active site by a collagen-mimicking hydroxamate structure [1].
A reduction in the size and number of metastatic foci in treated compared with the control animals was demonstrated by experimental metastases models against lung and breast cancer. The studies were carried out at doses of 100–500 mg/kg per day, and the agent induced gastrointestinal toxicity and weight loss, as well as hemorrhage, fibrosis, inflammation, and necrosis at particular ankle and knee tissues. Single oral doses of up to 800 mg were well tolerated and did not lead to obvious toxicity. Peak plasma concentrations can be detected within 1.5–3 hours after oral administration, and the elimination half-life was estimated as a range of 8–10 hours. No plasma accumulation was detected after an oral doses of 50–200 mg in continuous administration twice a day for 6 consecutive days [2,3].
Pharmacological studies demonstrated that marimastat is well absorbed from the gastrointestinal tract and exhibits a linear pharmacokinetic behavior. The minimum plasma concentration was found after exceeding 10 mg doses twice a day, which were sixfold greater than the required for inhibition of MMP in vitro. Complain to the patients treated with gemcitabine, the most effective chemotherapeutic agent against the nonmetastatic pancreatic cancer, the patients who received high doses of marimastat had a 1-year survival rates. It is encouraging that the patients with unresectable gastric cancer who were treated with marimastat show a modest increase in survival [1,2].
References:
1.Hidalgo M, Eckhardt SG, Development of matrix metalloproteinase inhibitors in cancer therapy. JOURNAL OF THE NATIONAL CANCER INSTITUTE. 2001, 93(3):178-193.
2.Coussens LM, Fingleton B , Matrisian LM , Cancer therapy - Matrix metalloproteinase inhibitors and cancer: Trials and tribulations. SCIENCE, 295 (5564): 2387-2392.
3.Van Wijngaarden J , Snoeks TJA , van Beek E, et al . An in vitro model that can distinguish between effects on angiogenesis and on established vasculature: Actions of TNP-470, marimastat and the tubulin-binding agent Ang-510. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2000, 391 (2): 1161-1165.
- 1. Chan ZC, Kwan HR, et al. "Site-directed MT1-MMP trafficking and surface insertion regulate AChR clustering and remodeling at developing NMJs."?Elife. 2020;9:e54379. PMID:32208136
- 2.Sapoznikov A, Gal Y, et al. "Early disruption of the alveolar-capillary barrier in a ricin-induced ARDS mouse model: neutrophil-dependent and -independent impairment of junction proteins." Am J Physiol Lung Cell Mol Physiol. 2019 Jan 1;316(1):L255-L268. PMID:30382767
| Storage | Store at -20°C |
| M.Wt | 331.41 |
| Cas No. | 154039-60-8 |
| Formula | C15H29N3O5 |
| Solubility | ≥2.8 mg/mL in H2O with gentle warming and ultrasonic; ≥20.43 mg/mL in EtOH; ≥80.1 mg/mL in DMSO |
| Chemical Name | (2R,3S)-N-[(2S)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]-N',3-dihydroxy-2-(2-methylpropyl)butanediamide |
| SDF | Download SDF |
| Canonical SMILES | CC(C)CC(C(C(=O)NO)O)C(=O)NC(C(=O)NC)C(C)(C)C |
| Shipping Condition | Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice. |
| General tips | We do not recommend long-term storage for the solution, please use it up soon. |
| Cell experiment [1]: | |
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Cell lines |
Human glioma cell lines U251 and GaMG. |
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Preparation method |
Soluble in DMSO > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reaction Conditions |
0.3 μM, 0.6 μM, 1.0 μM, 10 μM and 50 μM; 48 h or 6 days. |
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Applications |
In co-cultures of tumor spheroids derived from human glioma cell lines U251 and GaMG with RBA, marimastat strongly inhibits tumor invasion at concentrations of 10 μM. Marimastat (10 μM) significantly reduces cell proliferation by 54% and completely inhibits cell growth at 50 μM over 6 days. Also, marimastat (10 μM) reduces U251 spheroid growth by 65%. |
| Animal experiment [2]: | |
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Animal models |
Male 6-week-old C57BL6/J mice with liver fibrosis. |
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Dosage form |
100 mg/kg; twice daily via orogastric gavage; one week. |
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Applications |
Marimastat significantly reduces liver injury and inflammation but induces a 25% increase in collagen deposition following acute CCl4-administration. Marimastat inhibits MMP activities and reduces fibrolysis. In CCl4-induced chronic hepatic injury, marimastat significantly reduces serum alanine aminotransferase (ALT) levels by 14-fold and downregulates the mRNA levles of major pro-fibrogenic genes. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: [1]. Tonn JC, Kerkau S, Hanke A, et al. Effect of synthetic matrix-metalloproteinase inhibitors on invasive capacity and proliferation of human malignant gliomas in vitro. Int J Cancer, 1999, 80(5): 764-772. [2]. de Meijer VE, Sverdlov DY, Popov Y, et al. Broad-spectrum matrix metalloproteinase inhibition curbs inflammation and liver injury but aggravates experimental liver fibrosis in mice. PLoS One, 2010, 5(6): e11256. |
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| Description | Marimastat (BB-2516) is a broad spectrum inhibitor of matrix metalloprotease (MMP) with specificity towards MMP-9, MMP-1, MMP-2, MMP-14 and MMP-7 and IC50 values of 3 nM, 5 nM, 6 nM, 9 nM and 13 nM respectively. | |||||
| Targets | MMP-9 | MMP-1 | MMP-2 | MMP-14 | MMP-7 | |
| IC50 | 3 nM | 5 nM | 6 nM | 9 nM | 13 nM | |
Quality Control & MSDS
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