Diphenyl Phosphonate Inhibitors for the Urokinase-type Plasminogen Activator: Optimization of the P4 Position.
From: Laboratory of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, BE-2610 Antwerp, Belgium.
Journal of medicinal chemistry
- Publish Date: Sep 2006
- ISSN: 0022-2623
- Volume: 49
- Issue: 19
- Pages: 5785-93
- Medium: Print
- Language: English
- Citation (JAMA): Joossens Jurgen, Van der Veken Pieter, Surpateanu Georgiana, et al. Diphenyl Phosphonate Inhibitors for the Urokinase-type Plasminogen Activator: Optimization of the P4 Position.. J. Med. Chem. Sep 2006;49:5785-93
Abstract
This paper describes the structure-activity relationship in a series of tripeptidyl diphenyl phosphonate irreversible urokinase plasminogen activator (uPA) inhibitors, originally derived from an arginyltripeptide. uPA is considered an interesting target in anticancer drug design. The selectivity of these inhibitors for uPA is enhanced by the optimization of the P4 position. The most interesting compound shows an IC(50) of 5 nM, with a selectivity index of more than 3000 toward other Arg/Lys-specific proteases such as tissue-type plasminogen activator, plasmin, factor Xa, and thrombin. A synthetic strategy for the preparation of small libraries of diphenyl phosphonate analogues of capped tripeptides is described. It is shown that uPA is irreversibly inhibited, and interactions with the active site were modeled. Finally, a diparacetamol phosphonate analogue was developed to circumvent the release of cytotoxic phenol.
Mesh Headings (Keywords): Animals, Binding Sites, Humans, Mice, Models, Molecular, Oligopeptides, Phosphonic Acids, Structure-Activity Relationship, Urinary Plasminogen Activator
Check for Full Text / PubMed Unique Identifier (PMID): 16970403
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