BZB Group

MMP

CARBAMOYLPHOSPHONATES AS MATRIX METALLOPROTEINASE (MMP) INHIBITORS WITH ANTI-METASTASIS AND ANTI-RESTENOSIS ACTIVITY

Field: Cardiovascular, malignant, inflammatory, degenerative diseases and wound healing

Principal Investigators: Eli Breuer The School of Pharmacy, The Hebrew University of Jerusalem, Reuven Reich, The School of Pharmacy, The Hebrew University of Jerusalem

Patent Status: One of two patent applications has been filed. The second is in the final stages of preparations.

Abstract:(including Applications and Potential Markets):

The products of this project are applicable as drugs mainly in cancer and the cardiovascular field. Some of the products may find use in facilitating the healing of thermal and chemical wounds as well reducing scars in cosmetic surgery.

Background

       1.         Cancer dissemination The spread of malignant tumor cells from a primary neoplasm to distant organs where they multiply and form new foci is the major cause of death from cancer. To possess metastatic potential, a cell has to be able to invade the surrounding tissue, spread via lymphatics and/or the bloodstream, extravasate and multiply at secondary sites. Despite the different modalities of cancer treatment, no effective curative therapy of metastatic lesions is available. There is increasing evidence for a positive correlation between matrix metalloproteinase (MMP) activity and tumor cell invasion.

       2.         Restenosis. Coronary atherosclerosis and its clinical sequela continue to be the leading cause of mortality in the western society. Percutaneous transluminal coronary angioplasty (PTCA) has become a mainstay in the treatment of ischemic heart disease with an estimated over 1 million procedures performed annually in the US and Europe. PTCA procedures include balloon dilation, excisional atheroctomy, endoluminal stenting and laser ablation. Despite significant advances in reducing the acute complications of percutaneous revascularization procedures with pre-medications and better techniques, chronic restenosis of dilated lesions remains a serious and frequent problem, occurring in 20% to 30% of patients. It has been shown that matrix proteins and MMPs are contributing to the development of de novo  atherosclerotic plaques.

       3.         Matrix Metalloproteinases (MMPs) are a family of zinc enzymes that mediate the breakdown of connective tissue. The misregulation and overexpression of MMPs is a major factor in several diseases, including cancer metastasis and restenosis, and the MMP enzymes are therefore targets for therapeutic inhibitors especially in inflammatory, malignant, and degenerative diseases associated with excessive enzymatic activity. Inhibition of MMPs has therefore become the focus of numerous investigations.

MMP Inhibitors We discovered a new group of non-toxic MMP inhibitors, effective in nanomolar range. Our novel inhibitors differ from the currently known inhibitors in being water soluble, nontoxic and of simple, easily synthesized structure with considerable oral bioavailability.

Current Status:

1.            Cancer Metastasis

a. We have developed compounds that reduce lung metastasis formation and tumor burden in a murine melanoma model, to the extent of about 90 percent whether given intraperitoneally or orally.

b. Prostate tumor

One of our leading compounds was examined in an orthotopic prostate tumor model using mice injected with human prostate tumor cells transfected with a luciferase gene. This compound has caused a very substantial decrease both in the metastasis formation and in the sizes of the local tumors.

2.             Angiogenesis

New blood vessel formation is a critical step in the expansion and in dissemination of a given tumor. Tube formation has been show to be dependent on cellular proliferation and on expression of certain MMPs. Our compounds were examined in an in vitro capillary formation assay. Our results indicate that the compounds prevent tube formation and therefore present a dual efficiency-prevention of tumor cell invasion and prevention of capillary tube formation.

3.            Oral bioavailability

When a new type of drug is discovered and its efficacy is proven, it is necessary to develop a mode of administration that is convenient to the patient and achieves the desired therapeutic effect. Among the several possible routes of administration of drugs for systemic effect the oral route is the most convenient one. Therefore, it is of greatest importance that equal therapeutic effect has been reached when several of the tested compounds were administered orally or injected intraperitoneally, thus indicating on oral absorption. Histopathological examination showed no damage to the intestine epithelium following oral administration.

4.Toxicity

We have examined one of our most active compounds both in cancer and in restenosis, which also showed excellent oral bioavailability, for possible toxic effects. It was administered daily for two weeks in three doses: 50 mg/kg, 250 mg/kg and 500 mg/kg, to groups of 8 mice each. It was found that this compound showed no toxicity even at the daily dose of 500 mg/kg, which is 10 times higher than the therapeutic effective dose.

5. Dose response relationship

In the development of new drugs, it is important to find the most effective dose relative to the toxicity study,  and to rule out any possibility of a non-specific interaction of the drug with the experimental animal. Therefore, we performed a dose-response study with one of our prototype compounds that showed a dose dependent effect. These results indicate specificity and excellent safety margin in treatment of experimental animals.

7. Restenosis

A significant and marked inhibition of restenosis was observed in the hypercholesterolemic rabbit model of restenosis after 30 days following intraperitoneal treatment with 70 mg/kg divided in 5 doses over 8 days. The marked inhibition of restenosis is unparalleled to other therapeutic modalities in this model (various antiinflammatory or antiproliferative agents). Moreover, restenosis treatment by known MMP inhibitors such as Batimastat failed in same model. The mode of action of the new compound is probably via MMP inhibition and/or inhibition of angioneogenesis.

Future Plans:

The following additional work is needed in order to establish clinical utility of the compounds chosen for development:

    1st.       Synthesis of radio-labeled compounds for monitoring drug distribution.

   2nd.     Development of analytical methods for the new compounds in biological fluids and tissues.

    3rd.       Pharmacokinetic studies (ADME).

Keywords:        cancer, metastasis, angiogenesis, MMP-2, tumor, angioplasty, atherosclerosis, restenosis wound healing.

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Last modified: 03/16/04