title: 2,3-Dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid derivatives: a novel class of small molecule heparanase inhibitors.
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.
authors.affiliation: Department of Medicinal Chemistry, Celltech R&D Ltd, 4-10 The Quadrant, Abingdon Science Park, Abingdon, Oxfordshire, OX14 4YS, UK.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Courtney
authors.forename: Philip A
authors.initials: PA
authors.lastname: Hay
authors.forename: Richard T
authors.initials: RT
authors.lastname: Buck
authors.forename: Claire S
authors.initials: CS
authors.lastname: Colville
authors.forename: David W
authors.initials: DW
authors.lastname: Porter
authors.forename: David I C
authors.initials: DI
authors.lastname: Scopes
authors.forename: Faye C
authors.initials: FC
authors.lastname: Pollard
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Page
authors.forename: James M
authors.initials: JM
authors.lastname: Bennett
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Hircock
authors.forename: Edward A
authors.initials: EA
authors.lastname: McKenzie
authors.forename: Colin R
authors.initials: CR
authors.lastname: Stubberfield
authors.forename: Paul R
authors.initials: PR
authors.lastname: Turner
mesh_terms: 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
chemical_list: D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D005966:Glucuronidase; D000099175:Heparanase