An in Vivo Model for Screening Peptidomimetic Inhibitors of Gelatinase A
| Autor: | James O'Connell, Byron A. Boyce, Pari Antoniw, John Robert Porter, Andrew Mountain, Surinder K. Chander, Kenneth Millar, Richard Morphy, Barbara Mason, Neville Willmott, Nigel Robert Arnold Beeley, Joanna Leonard, Thomas Crabbe, Andrew T. Millican, Andrew J. P. Docherty |
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| Rok vydání: | 1995 |
| Předmět: |
Male
Gelatinase A Drug Evaluation Preclinical Administration Oral Pharmaceutical Science Matrix metalloproteinase Pharmacology Mice chemistry.chemical_compound Oral administration In vivo Animals Humans Hydroxamic acid Dose-Response Relationship Drug biology Metalloendopeptidases Biological activity Rats Kinetics Biochemistry chemistry Gelatinases Enzyme inhibitor biology.protein Systemic administration Matrix Metalloproteinase 2 Pleura Female Indicators and Reagents Peptides Injections Intraperitoneal |
| Zdroj: | Journal of Pharmaceutical Sciences. 84:404-409 |
| ISSN: | 0022-3549 |
| DOI: | 10.1002/jps.2600840405 |
| Popis: | 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 vivo activity 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 vivo activity 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 (ip) (to approximate systemic administration) and orally. For up to 2 h after ip administration, all inhibitors tested showed marked activity (> 90% inhibition) at 17 mumol/kg (approximately 10 mg/kg). This activity declined in a dose-responsive manner to insignificant levels at 0.67 mumol/kg (approximately 0.4 mg/kg). Aryl sulfonamides showed significant inhibition (> 50%) for up to 7 h after administration. A higher dosage (136 mumol/kg, approximately 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. |
| Databáze: | OpenAIRE |
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