The neuroprotective action of JNK3 inhibitors based on the 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole scaffold.
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.
Graczyk
Piotr P
PP
Eisai London Research Laboratories, University College London, Bernard Katz Building, Gower Street, London WC1E 6BT, UK. piotr_graczyk@eisai.net
Khan
Afzal
A
Bhatia
Gurpreet S
GS
Palmer
Vanessa
V
Medland
Darren
D
Numata
Hirotoshi
H
Oinuma
Hitoshi
H
Catchick
Jacqueline
J
Dunne
Angela
A
Ellis
Moira
M
Smales
Caroline
C
Whitfield
Jonathan
J
Neame
Stephen J
SJ
Shah
Bina
B
Wilton
Daniel
D
Morgan
Louise
L
Patel
Toshal
T
Chung
Raymond
R
Desmond
Howard
H
Staddon
James M
JM
Sato
Nobuaki
N
Inoue
Atsushi
A
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
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