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1-Aryl-3,4-dihydroisoquinoline inhibitors of JNK3
Authors:John A Christopher  Francis L Atkinson  Benjamin D Bax  Murray JB Brown  Aurélie C Champigny  Tsu Tshen Chuang  Emma J Jones  Julie E Mosley  James R Musgrave
Institution:1. GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK;2. GlaxoSmithKline R&D, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
Abstract:A series of 1-aryl-3,4-dihydroisoquinoline inhibitors of JNK3 are described. Compounds 20 and 24 are the most potent inhibitors (pIC50 7.3 and 6.9, respectively in a radiometric filter binding assay), with 10- and 1000-fold selectivity over JNK2 and JNK1, respectively, and selectivity within the wider mitogen-activated protein kinase (MAPK) family against p38α and ERK2. X-ray crystallography of 16 reveals a highly unusual binding mode where an H-bond acceptor interaction with the hinge region is made by a chloro substituent.
Keywords:
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