1400
B.-M. Swahn et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1397–1401
Table 3. Inhibition results for compounds 11–20 against JNK3, JNK1,
and p38a29
ently the induced fit binding into JNK3 was more favor-
able than for JNK1, and this can probably be explained
by the fact that the selectivity pocket has some differences
in the amino acid sequence in JNK3 compared to JNK1.
Especially Leu144 in JNK3 compared to Ileu106 in
JNK1 can play a crucial role in this respect. These 20-ani-
lino-4,40-bipyridine derivatives were shown to be potent
JNK3 inhibitors demonstrating good metabolic proper-
ties in vitro and in vivo as exemplified by compound 18.
Compound
JNK3 IC50
(nM)a
JNK1 IC50
(nM)a
p38 IC50
(nM)b
10d
11
12
13
14
15
16
17
18
20
21
22
23
44
15
235
9
219
88
n.m.
40
1280
82
n.m.
37
207
15
5
n.m.
85
n.m.
171
50
74
10
7
125
384
48
162
180
581
421
251
199
Acknowledgments
3
The authors thank Dr. Johanna Lindquist, Depart-
ment of Molecular Pharmacology AstraZeneca R&D
So¨derta¨lje, for determining the IC50 values for
JNK1, JNK3, and p38a, Dr. Stellan Swedmark,
Department of Research DMPK, for the metabolic
evaluations, and Dr. Stefan Geschwindner, Structural
Chemistry Laboratory, AstraZeneca R&D Mo¨lndal,
for support in protein production and initial crystalli-
zation studies.
9
55
8
122
152
6
n.m., not measured.
a Values are means of n P 2 determinations, standard deviation
6
10%.
b Values are means of n P 2 determinations, standard deviation
20%.
6
H
H
N
N
N
N
N
N
References and notes
F
O
O
1. Gupta, S.; Barrett, T.; Whitmarsh, A. J.; Cavanagh, J.;
Sluss, H. K.; Derijard, B.; Davis, R. J. EMBO J. 1996, 15,
2760.
N
N
H
H
O
O
18
19
2. Mohit, A. A.; Martin, J. H.; Miller, C. A. Neuron 1995, 14,
67.
H
3. Yang, D. D.; Kuan, C.-Y.; Whitmarsh, M. R.; Zheng, T.
S.; Davis, R. J.; Rakic, P.; Flavell, R. A. Nature 1997, 389,
865.
4. Kuan, C. Y.; Whitmarsh, A. J.; Yang, D. D.; Liao, G. H.;
Schloemer, A. J.; Dong, C.; Bao, J.; Banasiak, K. J.;
Haddad, G. G.; Flavell, R. A.; Davis, R. J.; Rakic, P.
PNAS 2003, 100, 15184.
5. Hunot, S.; Vila, M.; Teismann, P.; Davis, R. J.; Hirsch, E.
C.; Przedborski, S.; Rakic, P.; Flavell, R. A. PNAS 2004,
101, 665.
H
N
N
N
N
N
N
F
O
O
N
N
H
H
O
O
23
22
Figure 5. Tetrahydrofuranyl and tetrahydropyranyl analogues.
6. Chang, L. F.; Jones, Y.; Ellisman, M. H.; Goldstein, L. S.
B.; Karin, M. Dev. Cell. 2003, 4, 521.
indeed also the simplest molecules since they contained no
chiral center.
7. Kuan, C. Y.; Yang, D. D.; Roy, D. R. S.; Davis, R. J.;
Rakic, P.; Flavell, R. A. Neuron 1999, 22, 667.
8. (a) Manning, A. M.; Davis, R. J. Nat. Rev. 2003, 2, 554;
(b) Resnick, L.; Fennell, M. Drug Discov. Today 2004, 9,
932; (c) Kuan, C.-Y.; Burke, R. E. Curr. Drug Targets
CNS Neurol. Disord. 2005, 4, 63; (d) Liu, G.; Rondinone,
C. M. Curr. Opin. Invest. Drugs 2005, 6, 979.
9. Swahn, B.-M.; Huerta, F.; Kallin, E.; Malmstro¨m, J.;
Compound 18 displayed a good level of in vitro meta-
bolic stability (rat microsomes Clint = 12 lL/min/mg)
as well as good CaCo2 permeability (29.9 · 10ꢀ6 cm/s)
and IC50 was above 10 lM for the investigated 5 Cyp
isoforms. The compound was chosen as the candidate
for in vivo PK dosing in rat, and it demonstrated good
in vivo characteristics with a bioavailability of 16%
(Cl = 30 mL/min/kg; t1/2 = 4.7 h po).
¨
Weigelt, T.; Viklund, J.; Womack, P.; Xue, Y.; Ohberg, L.
Bioorg. Med. Chem. Lett. 2005, 15, 5095.
10. (a) Ruckle, T.; Biamonte, M.; Grippi-Vallotton, T.;
Arkinstall, S.; Cambet, Y.; Camps, M.; Chabert, C.;
Church, D. J.; Halazy, S.; Jiang, X.; Martinou, I.; Nichols,
A.; Sauer, W.; Gotteland, J.-P. J. Med. Chem. 2004, 47,
6921; (b) Gaillard, P.; Jeanclaude-Etter, I.; Ardissone, V.;
Arkinstall, S.; Cambet, Y.; Camps, M.; Chabert, C.;
Church, D.; Cirillo, R.; Gretener, D.; Halazy, S.; Nichols,
A.; Szyndralewiez, C.; Vitte, P.-A.; Gotteland, J.-P. J.
Med. Chem. 2005, 48, 4596; (c) Graczyk, P. P.; Khan, A.;
Bhatia, G. S.; Palmer, V.; Medland, D.; Numata, H.;
Oinuma, H.; Catchick, J.; Dunne, A.; Ellis, M.; Smales,
C.; Whitfield, J.; Neame, S. J.; Shah, B.; Wilton, D.;
Morgan, L.; Patel, T.; Chung, R.; Desmond, H.; Staddon,
In conclusion, a new series of JNK3 selective 20-anilino-
4,40-bipyridines was described. The binding mode of this
new series was confirmed by X-ray crystallographic
structures. The large selectivity for these compounds to
inhibit JNK3 compared to JNK1 can be attributed to
the fact that these compounds bind into the selectivity
pocket of JNK3, which has opened up by moving the
˚
side chain of Met146 by more than 2 A. This feature
has not been observed when ATP is bound to JNK3,
nor when the current series are bound to JNK1. Appar-