Aminopyridine-based c-Jun N-terminal kinase inhibitors with cellular activity and minimal cross-kinase activity.
The c-Jun N-terminal kinases (JNK-1, -2, and -3) are members of the mitogen activated protein (MAP) kinase family of enzymes. They are activated in response to certain cytokines, as well as by cellular stresses including chemotoxins, peroxides, and irradiation. They have been implicated in the pathology of a variety of different diseases with an inflammatory component including asthma, stroke, Alzheimer's disease, and type 2 diabetes mellitus. In this work, high-throughput screening identified a JNK inhibitor with an excellent kinase selectivity profile. Using X-ray crystallography and biochemical screening to guide our lead optimization, we prepared compounds with inhibitory potencies in the low-double-digit nanomolar range, activity in whole cells, and pharmacokinetics suitable for in vivo use. The new compounds were over 1,000-fold selective for JNK-1 and -2 over other MAP kinases including ERK2, p38alpha, and p38delta and showed little inhibitory activity against a panel of 74 kinases.
Szczepankiewicz
Bruce G
BG
Metabolic Disease Research, Global Pharmaceutical Research and Discovery Organization, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6098, USA. bruce.szczepankiewicz@abbott.com
Kosogof
Christi
C
Nelson
Lissa T J
LT
Liu
Gang
G
Liu
Bo
B
Zhao
Hongyu
H
Serby
Michael D
MD
Xin
Zhili
Z
Liu
Mei
M
Gum
Rebecca J
RJ
Haasch
Deanna L
DL
Wang
Sanyi
S
Clampit
Jill E
JE
Johnson
Eric F
EF
Lubben
Thomas H
TH
Stashko
Michael A
MA
Olejniczak
Edward T
ET
Sun
Chaohong
C
Dorwin
Sarah A
SA
Haskins
Kristi
K
Abad-Zapatero
Cele
C
Fry
Elizabeth H
EH
Hutchins
Charles W
CW
Sham
Hing L
HL
Rondinone
Cristina M
CM
Trevillyan
James M
JM
D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D006207:Half-Life; D006801:Humans; D048057:Mitogen-Activated Protein Kinase 10 / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D010766:Phosphorylation; D011487:Protein Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley
D000631:Aminopyridines; D048057:Mitogen-Activated Protein Kinase 10; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8