2jde

From Proteopedia

UROKINASE-TYPE PLASMINOGEN ACTIVATOR INHIBITOR COMPLEX WITH A 1-(7-SULPHOAMIDOISOQUINOLINYL)GUANIDINE

Overview

1-isoquinolinylguanidines were previously disclosed as potent and, selective inhibitors of urokinase-type plasminogen activator (uPA)., Further investigation of this template has revealed that incorporation of, a 7-sulfonamide group furnishes a new series of potent and highly, selective uPA inhibitors. Potency and selectivity can be achieved with, sulfonamides derived from a variety of amines and is further enhanced by, the incorporation of sulfonamides derived from amino acids. The binding, mode of these 1-isoquinolinylguanidines has been investigated by X-ray, cocrystallization studies. uPA inhibitor 26 was selected for further, evaluation based on its excellent enzyme potency (Ki 10 nM) and, selectivity profile (4000-fold versus tPA and 2700-fold versus plasmin)., In vitro, compound 26 is able to inhibit exogenous uPA in human chronic, wound fluid (IC50=0.89 microM). In vivo, in a porcine acute excisional, wound model, following topical delivery, compound 26 is able to penetrate, into pig wounds and inhibit exogenous uPA activity with no adverse effect, on wound healing parameters. On the basis of this profile, compound 26, (UK-371,804) was selected as a candidate for further preclinical, evaluation for the treatment of chronic dermal ulcers.

About this Structure

2JDE is a Single protein structure of sequence from [1]. Active as U-plasminogen activator, with EC number 3.4.21.73 Full crystallographic information is available from OCA.

Reference

Selective urokinase-type plasminogen activator inhibitors. 4. 1-(7-sulfonamidoisoquinolinyl)guanidines., Fish PV, Barber CG, Brown DG, Butt R, Collis MG, Dickinson RP, Henry BT, Horne VA, Huggins JP, King E, O'Gara M, McCleverty D, McIntosh F, Phillips C, Webster R, J Med Chem. 2007 May 17;50(10):2341-51. Epub 2007 Apr 21. PMID:17447747

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