2,3-Dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid derivatives: a novel class of small molecule heparanase inhibitors |
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| Authors: | Courtney Stephen M Hay Philip A 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 McKenzie Edward A Stubberfield Colin R Turner Paul R |
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| Institution: | Department of Medicinal Chemistry, Celltech R&D Ltd, 4-10 The Quadrant, Abingdon Science Park, Abingdon, Oxfordshire, OX14 4YS, UK. |
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| Abstract: | 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. |
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