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), 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.
Courtney
Stephen M
SM
Department of Medicinal Chemistry, Celltech R&D Ltd, 4-10 The Quadrant, Abingdon Science Park, Abingdon, Oxfordshire, OX14 4YS, UK.
Hay
Philip A
PA
Buck
Richard T
RT
Colville
Claire S
CS
Porter
David W
DW
Scopes
David I C
DI
Pollard
Faye C
FC
Page
Martin J
MJ
Bennett
James M
JM
Hircock
Margaret L
ML
McKenzie
Edward A
EA
Stubberfield
Colin R
CR
Turner
Paul R
PR
D002264:Carboxylic Acids / Q000737:chemistry* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D005966:Glucuronidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D000099175:Heparanase
D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D005966:Glucuronidase; D000099175:Heparanase