Discovery of potent, highly selective, and orally bioavailable pyridine carboxamide c-Jun NH2-terminal kinase inhibitors.
C-Jun NH2 terminal kinases (JNKs) are important cell signaling enzymes. JNK1 plays a central role in linking obesity and insulin resistance. JNK2 and JNK3 may be involved in inflammatory and neurological disorders, respectively. Small-molecule JNK inhibitors could be valuable tools to study the therapeutic benefits of inhibiting these enzymes and as leads for potential drugs targeting JNKs. In this report, we disclose a series of potent and highly selective JNK inhibitors with good pharmacokinetic profiles.
Zhao
Hongyu
H
Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6098, USA. Hongyu.zhao@abbott.com
Serby
Michael D
MD
Xin
Zhili
Z
Szczepankiewicz
Bruce G
BG
Liu
Mei
M
Kosogof
Christi
C
Liu
Bo
B
Nelson
Lissa T J
LT
Johnson
Eric F
EF
Wang
Sanyi
S
Pederson
Terry
T
Gum
Rebecca J
RJ
Clampit
Jill E
JE
Haasch
Deanna L
DL
Abad-Zapatero
Cele
C
Fry
Elizabeth H
EH
Rondinone
Cristina
C
Trevillyan
James M
JM
Sham
Hing L
HL
Liu
Gang
G
D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D018360:Crystallography, X-Ray; D006801:Humans; D066298:In Vitro Techniques; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D051379:Mice; D008861:Microsomes / Q000378:metabolism; D008958:Models, Molecular; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D000577:Amides; D011725:Pyridines; D048031:JNK Mitogen-Activated Protein Kinases