Aminopurine based JNK inhibitors for the prevention of ischemia reperfusion injury.
In this Letter we describe the optimization of an aminopurine lead (1) with modest potency and poor overall kinase selectivity which led to the identification of a series of potent, selective JNK inhibitors. Improvement in kinase selectivity was enabled by introduction of an aliphatic side chain at the C-2 position. CC-359 (2) was selected as a potential clinical candidate for diseases manifested by ischemia reperfusion injury.
Celgene Corporation, 4550 Towne Centre Court, San Diego, CA 92121, USA. vplantev@celgene.com
Véronique Plantevin
VP
Krenitsky
Mercedes
M
Delgado
Lisa
L
Nadolny
Kiran
K
Sahasrabudhe
Leticia
L
Ayala
Steven S
SS
Clareen
Robert
R
Hilgraf
Ronald
R
Albers
Adam
A
Kois
Kevin
K
Hughes
Jonathan
J
Wright
Jacek
J
Nowakowski
Elise
E
Sudbeck
Sutapa
S
Ghosh
Sogole
S
Bahmanyar
Philip
P
Chamberlain
Jeff
J
Muir
Brian E
BE
Cathers
David
D
Giegel
Li
L
Xu
Maria
M
Celeridad
Mehran
M
Moghaddam
Oleg
O
Khatsenko
Paul
P
Omholt
Jason
J
Katz
Sema
S
Pai
Rachel
R
Fan
Yang
Y
Tang
Michael A
MA
Shirley
Brent
B
Benish
Kate
K
Blease
Heather
H
Raymon
Shripad
S
Bhagwat
Ian
I
Henderson
Andrew G
AG
Cole
Brydon
B
Bennett
Yoshitaka
Y
Satoh
D015075:2-Aminopurine / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D020134:Catalytic Domain; D004285:Dogs; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D000882:Haplorhini; D020128:Inhibitory Concentration 50; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D015394:Molecular Structure; D011687:Purines / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D015427:Reperfusion Injury / Q000188:drug therapy / Q000201:enzymology*; D013329:Structure-Activity Relationship
C571666:CC-359; D004791:Enzyme Inhibitors; D011687:Purines; D015075:2-Aminopurine; D048031:JNK Mitogen-Activated Protein Kinases