Design and synthesis of disubstituted thiophene and thiazole based inhibitors of JNK.
From high throughput screening, we discovered compound 1, the prototype for a series of disubstituted thiophene inhibitors of JNK which is selective towards closely related MAP kinases p38 and Erk2. Herein we describe the evolution of these compounds to a novel class of thiophene and thiazole JNK inhibitors that retain favorable solubility, permeability, and P-gp properties for development as CNS agents for treatment of neurodegeneration. Compound 61 demonstrated JNK3 IC(50)=77 nM and retained the excellent broad kinase selectivity observed for the series.
Department of Chemical Sciences, Elan Pharmaceuticals, South San Francisco, CA 94080, USA. roy.hom@elan.com
Roy K
RK
Hom
Simeon
S
Bowers
Jennifer M
JM
Sealy
Anh P
AP
Truong
Gary D
GD
Probst
Martin L
ML
Neitzel
R Jeffrey
RJ
Neitz
Larry
L
Fang
Louis
L
Brogley
Jing
J
Wu
Andrei W
AW
Konradi
Hing L
HL
Sham
Gergely
G
Tóth
Hu
H
Pan
Nanhua
N
Yao
Dean R
DR
Artis
Kevin
K
Quinn
John-Michael
JM
Sauer
Kyle
K
Powell
Zhao
Z
Ren
Frédérique
F
Bard
Ted A
TA
Yednock
Irene
I
Griswold-Prenner
D000818:Animals; D015195:Drug Design; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D048057:Mitogen-Activated Protein Kinase 10 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D047428:Protein Kinase Inhibitors; D011804:Quinolines; D013844:Thiazoles; D013876:Thiophenes; D048057:Mitogen-Activated Protein Kinase 10; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8