2,3-Dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid derivatives: a novel class of small molecule heparanase inhibitors

A novel class of 2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acids are described as inhibitors of the endo-beta-glucuronidase heparanase. Several of the compounds, for example, 2-[4-propylamino-5-[5-(4-chloro)phenyl-benzoxazol-2-yl]phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid (9c...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2004-06, Vol.14 (12), p.3269-3273
Main Authors: COURTNEY, Stephen M, HAY, Philip A, MCKENZIE, Edward A, STUBBERFIELD, Colin R, TURNER, Paul R, BUCK, Richard T, COLVILLE, Claire S, PORTER, David W, SCOPES, David I. C, POLLARD, Faye C, PAGE, Martin J, BENNETT, James M, HIRCOCK, Margaret L
Format: Article
Language:English
Subjects:
Antineoplastic agents
Biological and medical sciences
Carboxylic Acids - chemistry
Carboxylic Acids - pharmacology
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
General aspects
Glucuronidase - antagonists & inhibitors
Glucuronidase - metabolism
Humans
Medical sciences
Miscellaneous
Pharmacology. Drug treatments
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Summary:A novel class of 2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acids are described as inhibitors of the endo-beta-glucuronidase heparanase. Several of the compounds, for example, 2-[4-propylamino-5-[5-(4-chloro)phenyl-benzoxazol-2-yl]phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid (9c), display potent heparanase inhibitory activity (IC(50) 200-500 nM) and have high selectivity (>100-fold) over human beta-glucuronidase. They also show anti-angiogenic effects. Such compounds should serve as useful biological tools and may provide a basis for the design of novel therapeutic agents.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2004.03.086