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:	eng
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