Development of amino-pyrimidine inhibitors of c-Jun N-terminal kinase (JNK): kinase profiling guided optimization of a 1,2,3-benzotriazole lead.
A series of amino-pyrimidines was developed based upon an initial kinase cross-screening hit from a CDK2 program. Kinase profiling and structure-based drug design guided the optimization from the initial 1,2,3-benzotriazole hit to a potent and selective JNK inhibitor, compound 24f (JNK1 and 2 IC(50)=16 and 66 nM, respectively), with bioavailability in rats and suitable for further in vivo pharmacological evaluation.
Roche Palo Alto, 3431 Hillview Ave., Palo Alto, CA 94304, USA. wyliepalmer@msn.com
Wylie S
WS
Palmer
Muzaffar
M
Alam
Humberto B
HB
Arzeno
Kung-Ching
KC
Chang
James P
JP
Dunn
David M
DM
Goldstein
Leyi
L
Gong
Bindu
B
Goyal
Johannes C
JC
Hermann
J Heather
JH
Hogg
Gary
G
Hsieh
Alam
A
Jahangir
Cheryl
C
Janson
Sue
S
Jin
R
R
Ursula Kammlott
Andreas
A
Kuglstatter
Christine
C
Lukacs
Christophe
C
Michoud
Linghao
L
Niu
Deborah C
DC
Reuter
Ada
A
Shao
Tania
T
Silva
Teresa A
TA
Trejo-Martin
Karin
K
Stein
Yun-Chou
YC
Tan
Parcharee
P
Tivitmahaisoon
Patricia
P
Tran
Paul
P
Wagner
Paul
P
Weller
Shao-Yong
SY
Wu
D000818:Animals; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D014230:Triazoles; C012771:benzotriazole; D048031:JNK Mitogen-Activated Protein Kinases