1-Aryl-3,4-dihydroisoquinoline inhibitors of JNK3 |
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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 |
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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 |
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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. |
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