The neuroprotective action of JNK3 inhibitors based on the 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole scaffold |
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| Authors: | Graczyk Piotr P Khan Afzal Bhatia Gurpreet S Palmer Vanessa Medland Darren Numata Hirotoshi Oinuma Hitoshi Catchick Jacqueline Dunne Angela Ellis Moira Smales Caroline Whitfield Jonathan Neame Stephen J Shah Bina Wilton Daniel Morgan Louise Patel Toshal Chung Raymond Desmond Howard Staddon James M Sato Nobuaki Inoue Atsushi |
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| Institution: | Eisai London Research Laboratories, University College London, Bernard Katz Building, Gower Street, London WC1E 6BT, UK. piotr_graczyk@eisai.net |
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| Abstract: | Imidazole-based structures of p38 inhibitors served as a starting point for the design of JNK3 inhibitors. Construction of a 6,7-dihydro-5H-pyrrolo1,2-a]imidazole scaffold led to the synthesis of the (S)-enantiomers, which exhibited p38/JNK3 IC50 ratio of up to 10 and were up to 20 times more potent inhibitors of JNK3 than the relevant (R)-enantiomers. The JNK3 inhibitory potency correlated well with inhibition of c-Jun phosphorylation and neuroprotective properties of the compounds in low K+-induced cell death of rat cerebellar granule neurones. |
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