Highly selective c-Jun N-terminal kinase (JNK) 2 and 3 inhibitors with in vitro CNS-like pharmacokinetic properties prevent neurodegeneration.
In this Letter, we describe the discovery of selective JNK2 and JNK3 inhibitors, such as 10, that routinely exhibit >10-fold selectivity over JNK1 and >1000-fold selectivity over related MAPKs, p38α and ERK2. Substitution of the naphthalene ring affords an isoform selective JNK3 inhibitor, 30, with approximately 10-fold selectivity over both JNK1 and JNK2. A naphthalene ring penetrates deep into the selectivity pocket accounting for the differentiation amongst the kinases. Interestingly, the gatekeeper Met146 sulfide interacts with the naphthalene ring in a sulfur-π stacking interaction. Compound 38 ameliorates neurotoxicity induced by amyloid-β in human cortical neurons. Lastly, we demonstrate how to install propitious in vitro CNS-like properties into these selective inhibitors.
Department of Medicinal Chemistry, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, United States. gary.probst@elan.com
Gary D
GD
Probst
Simeon
S
Bowers
Jennifer M
JM
Sealy
Anh P
AP
Truong
Roy K
RK
Hom
Robert A
RA
Galemmo
Andrei W
AW
Konradi
Hing L
HL
Sham
David A
DA
Quincy
Hu
H
Pan
Nanhua
N
Yao
May
M
Lin
Gergley
G
Tóth
Dean R
DR
Artis
Wes
W
Zmolek
Karina
K
Wong
Ann
A
Qin
Colin
C
Lorentzen
David F
DF
Nakamura
Kevin P
KP
Quinn
John-Michael
JM
Sauer
Kyle
K
Powell
Lany
L
Ruslim
Sarah
S
Wright
David
D
Chereau
Zhao
Z
Ren
John P
JP
Anderson
Frédérique
F
Bard
Ted A
TA
Yednock
Irene
I
Griswold-Prenner
D000631:Aminopyridines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D001665:Binding Sites; D002490:Central Nervous System / Q000378:metabolism; D003198:Computer Simulation; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D048057:Mitogen-Activated Protein Kinase 10 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000188:drug therapy*; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014227:Triazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use
D000631:Aminopyridines; D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D014227:Triazines; D048057:Mitogen-Activated Protein Kinase 10; D048056:Mitogen-Activated Protein Kinase 9