| Autor: |
Chander, Surinder K., Antoniw, Pari, Beeley, Nigel R.A., Boyce, Byron, Crabbe, Thomas, Docherty, Andrew J.P., Leonard, Joanna, Mason, Barbara, Millar, Kenneth, Millican, Andrew T., Morphy, Richard, Mountain, Andrew, O'Connell, James, Porter, John R., Willmott, Neville |
| Zdroj: |
Journal of Pharmaceutical Sciences; April 1995, Vol. 84 Issue: 4 p404-409, 6p |
| Abstrakt: |
Gelatinase A, a matrix metalloproteinase, is frequently associated with human solid tumors, and its secretion and activation in the tumor milieu is considered important in the process of angiogenesis, invasion, and metastasis. Consequently, metalloproteinase inhibitors may be of value in the therapy of cancer as well as other disease states involving tissue remodeling and release of biologically active peptide/protein by proteolytic cleavage. Here we describe the development of a rapid screening assay for in vivoactivity of peptidomimetic inhibitors of gelatinase A that involves assessment of inhibition of an enzyme–substrate reaction in a circumscribed body compartment, the mouse pleural cavity. As examples of the utility of this assay, in vivoactivity of the aryl sulfonamide, sulfamyl urea, morpholino and carboxylic acid functionality at the P3′ position of a series of hydroxamic acid inhibitors was examined after administration both intraperitoneally (lp) (to approximate systemic administration) and orally. For up to 2h after lp administration, all inhibitors tested showed marked activity (>90% inhibition) at 17 μmol/kg (∼10 mg/kg). This activity declined in a dose‐responsive manner to insignificant levels at 0.67 μmol/kg (∼0.4 mg/kg). Aryl sulfonamides showed significant inhibition (>50%) for up to 7h after administration. A higher dosage (136 μmol/kg, ∼80 mg/kg) was required to reveal oral activity, which was observed only with morpholino compounds (>50% inhibition). Thus, the model described may be of value in the identification of orally active gelatinase A inhibitors. |
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