title: The neuroprotective action of JNK3 inhibitors based on the 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole scaffold.
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-pyrrolo[1,2-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.
authors.affiliation: Eisai London Research Laboratories, University College London, Bernard Katz Building, Gower Street, London WC1E 6BT, UK. piotr_graczyk@eisai.net
authors.forename: Piotr P
authors.initials: PP
authors.lastname: Graczyk
authors.forename: Afzal
authors.initials: A
authors.lastname: Khan
authors.forename: Gurpreet S
authors.initials: GS
authors.lastname: Bhatia
authors.forename: Vanessa
authors.initials: V
authors.lastname: Palmer
authors.forename: Darren
authors.initials: D
authors.lastname: Medland
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Numata
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Oinuma
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Catchick
authors.forename: Angela
authors.initials: A
authors.lastname: Dunne
authors.forename: Moira
authors.initials: M
authors.lastname: Ellis
authors.forename: Caroline
authors.initials: C
authors.lastname: Smales
authors.forename: Jonathan
authors.initials: J
authors.lastname: Whitfield
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Neame
authors.forename: Bina
authors.initials: B
authors.lastname: Shah
authors.forename: Daniel
authors.initials: D
authors.lastname: Wilton
authors.forename: Louise
authors.initials: L
authors.lastname: Morgan
authors.forename: Toshal
authors.initials: T
authors.lastname: Patel
authors.forename: Raymond
authors.initials: R
authors.lastname: Chung
authors.forename: Howard
authors.initials: H
authors.lastname: Desmond
authors.forename: James M
authors.initials: JM
authors.lastname: Staddon
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Sato
authors.forename: Atsushi
authors.initials: A
authors.lastname: Inoue
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002531:Cerebellum / Q000166:cytology; D007093:Imidazoles; D048057:Mitogen-Activated Protein Kinase 10 / Q000037:antagonists & inhibitors*; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000494:pharmacology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D007093:Imidazoles; D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D048057:Mitogen-Activated Protein Kinase 10; D048051:p38 Mitogen-Activated Protein Kinases