Highly selective c-Jun N-terminal kinase (JNK) 3 inhibitors with in vitro CNS-like pharmacokinetic properties II. Central core replacement

Article abstract of DOI:10.1016/j.bmcl.2011.04.074

In this Letter, we describe the evolution of selective JNK3 inhibitors from 1, that routinely exhibit >10-fold selectivity over JNK1 and >1000-fold selectivity over related MAPKs. Strong SAR was found for substitution of the naphthalene ring, as well as f

Full text of DOI:10.1016/j.bmcl.2011.04.074

Bioorganic & Medicinal Chemistry Letters 21 (2011) 3726–3729
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Highly selective c-Jun N-terminal kinase (JNK) 3 inhibitors with in vitro CNS-like
pharmacokinetic properties II. Central core replacement
R. Jeffrey Neitz a, , Andrei W. Konradi a, Hing L. Sham a,b, Wes Zmolek d, Karina Wong d, Ann Qin d,
⇑
Colin Lorentzen d, David Nakamura d, Kevin P. Quinn d, John-Michael Sauer d, Kyle Powell e,
Lany Ruslim e, David Chereau e, Zhao Ren e, John Anderson e, Frédérique Bard e,
Ted A. Yednock a,b,c,d,e, Irene Griswold-Prenner e
a Department of Medicinal Chemistry, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, United States
b Department of Process and Analytical Chemistry, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, United States
c Department of Molecular Design, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, United States
d Department of Lead Finding, Drug Disposition, and Safety Evaluation, Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080, United States
e Department of Biology, Elan Pharmaceuticals, 1000 Gateway Boulevard, South San Francisco, CA 94080, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
In this Letter, we describe the evolution of selective JNK3 inhibitors from 1, that routinely exhibit >10-
fold selectivity over JNK1 and >1000-fold selectivity over related MAPKs. Strong SAR was found for sub-
stitution of the naphthalene ring, as well as for inhibitors adopting different central scaffolds. Significant
potency gains were appreciated by inverting the polarity of the thione of the parent triazolothione 1,
resulting in potent compounds with attractive pharmacokinetic profiles.
Received 12 January 2011
Revised 15 April 2011
Accepted 19 April 2011
Available online 27 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
The c-Jun N-terminal kinases (JNKs 1–3) are serine/threonine
targeted members of the mitogen-activated protein kinases (MAP-
Ks).1 JNK3 is concentrated primarily in the brain while JNK1 and
JNK2 are distributed widely. JNK1 performs important functions
in maintenance and regulation of the central nervous system
(CNS), and has been of interest as a target for inhibition in the
periphery to impact metabolic disorders.2 JNK2, JNK3, and dual
JNK2 and JNK3 knockout mice all show phenotypic resistance to
induced neurodegeneration.3 Inhibition of JNK2 and JNK3 thus
may provide a means to directly impact Alzheimer’s disease and
Parkinson’s disease, among others.4
JNK3 IC50 = 1.07uM
JNK2 IC50 = 7.28uM
JNK1 IC50 = 2.95uM
OxMet (%R): m=100, h=100
GlucMet (%R)= m=1, h=8
P-gp Efflux = 1.12
S
N
NH
N
N
1
solubility = 100uM
Figure 1. JNK3 kinase inhibitor: screening hit.6,7
Compound 1 was identified from our in-house compound
collection during a screening campaign to identify compounds
with JNK activity, and broad selectivity against other kinases
(Fig. 1). SAR for the triazolone variants of 1 have been previously
disclosed.5 Herein we describe variously substituted naphthyls
and pyridyls appended to the triazolothione, as well as the substi-
tution of the central ring by a series of heterocycles.
Exploration of the SAR began by substituting the napthyl ring
with quinolines in an attempt to ameliorate glucuronidation and
enhance potency, while retaining the excellent solubility and
p450 stability. Syntheses of these analogs were accomplished
using the two-step procedure described in Scheme 1. Each quino-
line derivative lost nearly all activity versus the JNKs (Table 1).
Substitution off the pyridyl ring was also explored. Again the SAR
here was very sharp, with a 30Â loss in JNK3 activity seen with
the addition of a simple methyl group to the c-position (5).
Potency gains were appreciated here for derivatives with nitro-
gen substitution at the c-position (as was similarly the case with
the triazolone derivatives disclosed previously),5 albeit at the ex-
pense of solubility.
Having determined useful appendages for increasing target po-
tency, we next set about to probe the triazolothione core (Table 2).
To our surprise, replacing the triazolothione with a simple triazole
(14) resulted in only a 10Â loss in potency. Indeed, this triazole
was 3Â more potent than the parent triazolone.5
Synthesis of the most active analog 14 was accomplished in two
steps (Scheme 2).
Next, wholesale substitution of the central ring with other het-
erocycles was explored (Table 3).
Various regiochemical permutations of pyrazoles, triazoles,
⇑
Corresponding author.
E-mail address: jeff.neitz@gmail.com (R. Jeffrey Neitz).
and
a tetrazole were synthesized and found to exhibit a
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.04.074

R. Jeffrey Neitz et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3726–3729
3727
S
N
N
S
N
H
H
b
a
NH
N
N
NH2
N
H
N
H
N
O
O
3
2
N
1
Scheme 1. Reagents and conditions: (a) 2-naphthylisothiocyanate, MeOH, 70 °C, microwave, 15 min; (b) 5% KOH aq, 110 °C, microwave, 15 min (75% overall).
Table 1
SAR of triazolothionesa
β
α
S
N
NH
N
B
N
A
#
a
b
A
B
JNK3 IC50
JNK2 IC50
JNK1 IC50
Soln
1
4
5
6
7
8
9
10
11
12
C–H
N
C–H
N
C–H
C–H
C–H
C–H
C–H
C–H
C–H
C–H
C–H
C–H
C–H
C–H
N
C–H
C–H
C–H
C–H
C–H
C–Me
C–Me
C–H
C–Br
C–H
C–NH2
CNH-cHex
C–NH-methylcProp
C–H
C–H
C–H
C–H
C–F
C–H
C–H
C–H
C–H
C–H
0.559
>50
14.8
>50
27.4
>50
31.8
1.03
0.0522
0.945
2.98
>50
15.3
>50
34.6
>50
>50
0.504
0.0665
2.25
12.5
>50
>50
>50
>50
>50
>50
24.3
>50
>50
100
100
100
100
35
35
15
100
5
35
a
Values are in
lM and means of at least three experiments at 10
lM ATP concentration.
Table 2
SAR of triazole perturbationsa
X
N
N
N
N
#
X
JNK3 IC50
(l
M)
JNK2 IC50
(lM)
JNK1 IC50
(lM)
Solubility (lM)
1
C–SH
C–CF3
C–H
C–Me
N
0.559
>50
2.98
>50
19.0
46.2
>50
>50
34.0
12.5
>50
>50
>50
>50
>50
>50
100
15
35
100
15
78
13
14
15
16
17
18
4.48
18.3
49.1
30.4
14.9
C–Cl
C–N–NH2
65
a
Values are means of at least three experiments at 10
lM ATP concentration.
O
O
H
Attempts to substitute the five-membered ring core with a
six-membered pyrimidine scaffold failed to track in potency
(Table 4). Both 29 and 31 were accessed from intermediate 36
(Scheme 3).
a
N
H
b
N
NH2
N
N
H
N
H
N
N
O
N
19
20
N
Permeability and P-gp efflux are both critical in vitro measures
to evaluate the potential of a molecule to access the parenchyma of
the brain and be an effective CNS therapeutic. Table 5 illustrates
the moderation of these properties for our most potent com-
pounds. Moderate metabolic stability was observed in a micro-
somal assay. Metabolism via glucuronidation was not found to be
a problem.
In summary, we have succeeded in replacing the triazolothione
core of the screening hit with simple pyrazole which shows mod-
erate CNS properties with a 2Â increase in potency.
14
Scheme 2. Reagents and conditions: (a) ethylformate (10 equiv), 110 °C (45%); (b)
2-aminonaphthalene, MeOH, 110 °C (63%).
relatively flat SAR, excepting the potency gains seen for the H-
bond donating triazole 28 and pyrazole 29. These analogs also
retained 20Â selectivity over JNK1, however oxidative metabo-
lism was pervasive.

3728
R. Jeffrey Neitz et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3726–3729
Table 3
SAR of scaffold variationa
X
α
δ
β
γ
N
#
a
b
c
d
X
JNK3 IC50
(l
M)
JNK2 IC50
(l
M)
JNK1 IC50
(l
M)
Ox. Metb (%m, %h)
21
22
23
24
25
26
27
28
29
C
C
C
N
C
N
N
C
C
N
N
N
C
N
C
C
C
C
N–H
N–H
N–H
C–H
N–H
N–H
C–H
N–H
C–H
N
N
C–Cl
C–H
C–H
N
N
C–H
N
12.6
4.81
2.46
1.23
>50
1.91
2.67
0.364
0.245
37.9
18.6
9.31
4.88
>50
6.39
9.14
1.22
0.864
>50
>50
41.9
>50
>50
>50
>50
6.85
7.15
0, 5
0, 12
0, 2
11, 58
0, 16
0, 18
n/a
2, 44
1, 52
C–H
C–H
N
C–H
N
N
N–H
N
N
a
Values are means of at least three experiments at 10
Percent remaining after 30 min incubation with liver microsomes (m = mouse and h = human).
l
M ATP concentration.
b
Table 4
Table 5
In vitro pharmacokinetic properties
SAR of pyrimidyl scaffolda
N
X
Het
N
N
N
#
X
JNK3 IC50
JNK2 IC50
JNK1 IC50
OxMetb (m, h)
P-gp6
efflux
6
#
Het
JNK3 IC50
Papp
OxMet GlucMet
(m, h)a
31
32
H
OH
4.13
1.51
18.1
3.89
>50
31.8
0, 29
72, 76
l
M
(nm/s)
H
N
a
Values are in
concentration.
lM and means of at least three experiments at 10 lM ATP
29
28
14
22
0.245
0.364
4.48
169
1, 52 100, 73
45, 44 n/a
1.14
n/a
n/a
n/a
N
b
Percent remaining after 30 min incubation with liver microsomes (m = mouse
and h = human).
H
N
152
306
379
N
N
N
N
O
b
76, 100 87, 100
22, 12 90, 78
a
N
N
N
OH
OMe
35
O
N
34
33
O
4.81
N
N
H
N
N
d
N
32
1.51
165
80, 76 n/a
n/a
O
N
H
NMe2
N
a
c
Percent remaining after 30 min incubation with liver microsomes for ox. and
29
31
60 min for gluc. (m = mouse and h = human).
O
N
36
N
e
Supplementary data
N
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.04.074.
N
Scheme 3. Reagents and conditions: (a) (1) oxaloylchloride, (2) HN(OMe)Me (80%);
(b) LDA, 4-methylpyridine, 0 °C (65%); (c) DMF/DMA (2 equiv), DCE; (d) hydrazine,
90 °C (70% for two steps); (e) amidine 90 °C (35% for two steps).
References and notes
1. (a) Siddiqui, M. S.; Reddy, P. A. J. Med. Chem. 2010, 53, 3005; (b) Bogoyevitch, M.
A.; Ngoei, K. R. W.; Zhao, T. T.; Yeap, Y. Y. C.; Ng, D. C. H. Biochim. Biophys. Acta
2010, 1804, 463; (c) Haeusgen, W.; Boehm, R.; Zhao, Y.; Herdegen, T.; Waetzig, V.
Neuroscience 2009, 161, 951; (d) LoGrasso, P.; Kamenecka, T. Mini-Rev. Med.
Chem. 2008, 8, 755; (e) Bogoyevitch, M. A.; Arthur, P. G. Biochim. Biophys. Acta
2008, 1784, 76; (f) Bogoyevitch, M. A.; Kobe, B. Microbiol. Mol. Biol. Rev. 2006, 70,
1061; (g) Karin, M.; Gallagher, E. IUBMB Life 2005, 57, 283.
Acknowledgments
We would like to thank Michael P. Bova, Danny Tam, Sarah
Wright, Carla Ramos, and Robert Arslanian for their contributions
to this work.
2. Chang, L.; Jones, Y.; Ellisman, M. H.; Goldstein, L. S.; Karin, M. Dev. Cell 2003, 4,
521.

R. Jeffrey Neitz et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3726–3729
3729
3. (a) Hunot, S.; Vila, M.; Teismann, P.; Davis, R. J.; Hirsch, E. C.; Przedborski, S.;
Rakic, P.; Flavell, R. A. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 665; (b) Yang, D. D.;
Kuan, C.-Y.; Whitmarsh, A. J.; Rincón, M.; Zheng, T. S.; Davis, R. J.; Rakic, P.;
Flavell, R. A. Nature 1997, 389, 865.
4. (a) Borsello, T.; Forloni, G. Curr. Pharm. Des. 2007, 13, 1875; (b) Wang, W.; Ma, C.;
Mao, Z.; Li, M. Drug News Perspect. 2004, 17, 646; (c) Resnick, L.; Fennell, M. Drug
Discovery Today 2004, 9, 932; (d) Harper, S. J.; Wilkie, N. Expert Opin. Ther. Targets
2003, 7, 187; (e) Manning, A. M.; Davis, R. J. Nat. Rev. Drug Discov. 2003, 2,
554.
K. P.; Sauer, J.-M.; Powell, K.; Ruslim, L.; Wright, S.; Chereau, D.; Ren, Z.;
Anderson, J. A.; Bard, F.; Yednock, T. A.; Griwold-Prenner, I. Bioorg. Med. Chem.
Lett. 2011, 21, 315.
6. For conditions of in vitro pharmacokinetic assays, see: Truong, A. P.; Aubele, D.
A.; Probst, G. D.; Neitzel, M. L.; Semko, C. M.; Bowers, S.; Dressen, D.; Hom, R. K.;
Konradi, A. W.; Sham, H. L.; Garofalo, A. W.; Keim, P. S.; Wu, J.; Dappen, M. S.;
Wong, K.; Goldbach, E.; Quinn, K. P.; Sauer, J.-M.; Brigham, E. F.; Wallace, W.;
Nguyen, L.; Hemphill, S. S.; Bova, M. P.; Basi, G. Bioorg. Med. Chem. Lett. 2009, 19,
4920.
5. Probst, G. P.; Bowers, S.; Sealy, J. M.; Truong, A. P.; Hom, R. K.; Galemmo, Robert
A.; Konradi, A. K.; Sham, H. L.; Quincy, D. A.; Pan, H.; Yao, N.; Lin, M.; Toth, G.;
Artis, D. R.; Zmolek, W.; Wong, K.; Qin, A.; Lorentzen, C.; Nakamura, D. F.; Quinn,
7. Details of the TR-FRET enzyme inhibition assay may be found in the
Supplementary data for Hom, R. K. et al Bioorg. Med. Chem. Lett. 2009, 20,
7303. Kinase selectivity data for 1 can be found in the Supplementary data.