Highly selective c-Jun N-terminal kinase (JNK) 2 and 3 inhibitors with in vitro CNS-like pharmacokinetic properties prevent neurodegeneration

Article abstract of DOI:10.1016/j.bmcl.2010.11.010

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.

Full text of DOI:10.1016/j.bmcl.2010.11.010

Bioorganic & Medicinal Chemistry Letters 21 (2011) 315–319
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Highly selective c-Jun N-terminal kinase (JNK) 2 and 3 inhibitors with in vitro
CNS-like pharmacokinetic properties prevent neurodegeneration
Gary D. Probst a, , Simeon Bowers a, Jennifer M. Sealy a, Anh P. Truong a, Roy K. Hom a,
⇑
Robert A. Galemmo Jr. a, Andrei W. Konradi a, Hing L. Sham a,b, David A. Quincy b, Hu Pan c, Nanhua Yao c,
May Lin c, Gergley Tóth c, Dean R. Artis c, Wes Zmolek d, Karina Wong d, Ann Qin d, Colin Lorentzen d,
David F. Nakamura d, Kevin P. Quinn d, John-Michael Sauer d, Kyle Powell e, Lany Ruslim e,
Sarah Wright e, David Chereau e, Zhao Ren e, John P. 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 discovery of selective JNK2 and JNK3 inhibitors, such as 10, that routinely
Received 23 September 2010
Revised 27 October 2010
Accepted 1 November 2010
Available online 5 November 2010
exhibit >10-fold selectivity over JNK1 and >1000-fold selectivity over related MAPKs, p38
a 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 sul-
fide interacts with the naphthalene ring in a sulfur-
p stacking interaction. Compound 38 ameliorates
Keywords:
JNK inhibitor
Selective
Kinase
neurotoxicity induced by amyloid-b in human cortical neurons. Lastly, we demonstrate how to install
propitious in vitro CNS-like properties into these selective inhibitors.
Ó 2010 Elsevier Ltd. All rights reserved.
The c-Jun N-terminal kinases (JNKs), a.k.a. stress-activated pro-
tein kinases (SAPKs), are serine/threonine targeted members of the
mitogen-activated protein kinases (MAPKs).1 Three variants in the
JNK family are known, JNK1, JNK2, and, JNK3; JNK3 is localized pri-
marily in the brain while JNK1 and JNK2 are expressed ubiqui-
tously. JNK1 performs important functions in maintenance and
regulation of the central nervous system (CNS), thus JNK1 knock-
out mice suffer from progressive neurodegeneration.2 JNK2, JNK3,
and dual JNK2 and JNK3 knockout mice were resistant to induced
neurodegeneration when compared to their wild type counter-
parts.3 Since JNK2 and JNK3 both play a prominent role in apopto-
sis, they are potential therapeutic targets for neurodegenerative
disorders, such as Alzheimer’s disease, Parkinson’s disease, Hun-
tington’s disease, amyotrophic lateral sclerosis, and cerebral
ischaemia.4 Indeed, administration of JNK inhibitors in vivo confers
protection against neuronal degradation.5 In order to avoid unto-
ward side effects, a selective inhibitor6 would be necessary (e.g.,
H
N
N
N
Cl
Cl
N
N
N
N
NH
N
S
1
JNK3 96% inhibition
@ 10 uM of 1
c-Raf 65% inhibition
@ 10 uM of 1
NH
2
JNK3 IC50= 1.6 nM
p38α IC50= 4.0 nM
[ATP]= 1 uM 10b
6d
[ATP]=kinase K m
Figure 1. JNK3 kinase inhibitors and selectivity.
p38a
, a closely related MAPK,7 is involved in maintaining synaptic
plasticity in the CNS).8
Compound 1 was discovered from our in-house compound col-
lection during a screening campaign to identify compounds with
JNK activity, and broad selectivity against other kinases (Fig. 1).
Of the 262 kinases screened only JNK3 and c-Raf had their activity
⇑
Corresponding author.
E-mail address: gary.probst@elan.com (G.D. Probst).
reduced by more than 50% at 10 l
M of 1.9 This was all the more
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.11.010

316
G. D. Probst et al. / Bioorg. Med. Chem. Lett. 21 (2011) 315–319
surprising since the closely related analog 210 with the 1,2-dichlo-
CHO
H
H
NH2
robenzene, a naphthalene ring isostere,11 does not display much
a-b
N
N
NH2
+
selectivity over p38
a
or JNK isoforms. This prompted us to investi-
O
N
Br
gate if we could improve the activity against JNK while maintain-
ing the selectivity profile. We deemed the thiourea to be
pharmaceutically unacceptable,12 thus the first operation was to
replace the thiocarbonyl with a carbonyl so the triazolone 9 (Ta-
ble 1) became the starting point.
3
4
5
H
N
N
Br
N
R
c
d
N
N
N
NH
N
6
7
NH
O
Our first priority was to append an amino group bearing a
hydrophobic substituent at the 2-position of the pyridine which
should lead to a substantial increase in potency based on the liter-
ature precedent.10 A halide at the 2-position of the pyridyl ring
would allow for the rapid synthesis of analogs via transition me-
tal-mediated cross-couplings. Synthesis of the key intermediate 6
was accomplished in an expedient manner (Scheme 1). Commer-
cially available starting material 3 was reacted with triphosgene
forming an isocyanate that was trapped with hydrazine to yield
the semicarbazide 4. Condensation of 4 with the aldehyde 5 affor-
ded the semicarbazone that was subjected to an in situ oxidative
ring closure.13 This route furnished copious amounts of the syn-
thetically versatile bromide 6 for further elaboration. The preferred
method to introduce the amino group was through the use of pal-
ladium catalyzed cross-coupling methodologies.14
O
Scheme 1. Reagents and conditions: (a) triphosgene, PhMe, 95 °C; (b) hydrazine,
PhMe, 84% over two steps; (c) EtOH, 2 h, then K3PO4, 95 °C, 5 min, then K3Fe(CN)6,
H2O, 95 °C, 48%; (d) H2N–R, Pd2dba3–CHCl3, BINAP or Xantphos, NaO-tBu or Cs2CO3,
PhMe, 80 °C.
(Table 1). The thiocarbonyl analog of 10 is equipotent (not shown).
Gratifyingly, no ERK2 or p38
a activity was evident, and the com-
pound was selective for JNK2 and JNK3 over JNK1. Additionally, a
screening against a panel of 38 kinases demonstrated that 10
maintained a clean profile.9 Only when a heteroatom was placed
at the 3-position of the newly appended ring, 11 and 18, was
ERK2 activity observed. In fact, a panel screen against the same
38 kinases with 11 exposed a deterioration in the selectivity of
inhibitor.9 Five-membered rings, 13 and 19, displayed moderate
potency against JNK2 and JNK3 but lost all activity against JNK1
The first target was the cyclohexylamine 10 which resulted in
nearly 1000-fold increase in potency relative to the parent 9
Table 1
SAR of amino groups at the pyridyl 2-positiona
N
R
N
N
NH
8
O
#
R
JNK3 IC50
16
(l
M)
JNK2 IC50
32
(lM)
JNK1 IC50
>50
(lM)
ERK2 IC50
>50
(lM)
P38
a IC50 (lM)
9
–H
>50
H
10
0.024
0.032
0.085
0.069
0.13
0.25
1.0
>50
22
>50
>50
>50
N
O
H
N
11b
12
0.74
1.8
H
N
>50
O
H
N
13
14
15
16
0.13
0.35
0.22
0.39
0.47
>50
1.8
3.9
5.7
>50
>50
>50
>50
>50
>50
>50
>50
H
N
0.070
0.13
H
N
H
N
0.061
N
H
N
17
18
0.040
0.25
0.11
0.95
2.2
3.3
>50
14
>50
>50
N
H
N
N
S
H
N
19
20
21
0.21
3.9
0.65
>5.0
1.5
>50
>5.0
7.2
>50
>5.0
>50
>50
NH
>5.0
>50
NH
0.41
O
NH
22
23
0.12
0.59
0.44
4.4
4.6
>50
>50
>50
>50
O
NH
>50
O
a
Values are means of at least three experiments at 10
1:1 mixture of enantiomers.
lM ATP concentration, see Supplementary data for experimental details.
b

G. D. Probst et al. / Bioorg. Med. Chem. Lett. 21 (2011) 315–319
317
in addition to lack of discernable activity against ERK2 or p38
attempted to induce p38 activity with (S)- -methylbenzylamine,
20, since this piece is known to be quite active against p38 on
a. We
H
N
N
N
N
Br
R2
a
a
a-b
a
similar templates,7 but the naphthalene ring remained the domi-
nant factor in determining the selectivity. Aryl rings, 16 and 17,
in place of saturated ring systems afforded inhibitors with compa-
rable activity and selectivity. Amides 21–23 were also explored but
the results for JNK2 and JNK3 activity were sub-optimal.
N
N
N
NH
6
31
N
O
O
R1
Scheme 2. Reagents and conditions: (a) HOR1, DIAD, polymer support-PPh2, THF,
0 °C, ca. 50%; (b) H2NR2, Pd2dba3–CHCl3, BINAP, NaO-tBu, PhMe.
Modifications of the naphthalene ring were also explored
(Table 2). The 4-aminopyran was used to prepare analogs due to
better in vitro pharmacokinetic properties associated with it. This
will be discussed vide infra (Table 4). Fluoride substitution at R1,
the 6-postion, on the naphthalene ring of 25 was potency neutral
for JNK2 and JNK3. However, substituents other than fluorine 26
and 27 at the 6-position led to a decrease in potency. The 8-posi-
tion, R2, was more tolerant of substitution as demonstrated by ana-
logs 28–30. The chloride 30 had the JNK3 activity enhanced by
sixfold and was approximately 10-fold selective over both JNK1
and JNK2.
Table 3
SAR of substitution on the triazolonea
H
N
N
X
N
N
N
32
O
R
#
X
R
JNK3
IC50
JNK2
IC50
M)
JNK1
IC50
ERK2
IC50
P38
IC50
M)
a
Lastly, N-substitutions on the triazolone were explored. The
triazolone ring was N-alkylated via a Mitsunobu reaction with
intermediate 6 and the amino group was appended subsequently
(vida supra Scheme 2).
(l
M)
(l
(l
M)
(lM)
(l
10
12
CH2 –H
0.024
0.085
0.069
0.25
1.0
1.8
>50
>50
>50
>50
O
–H
33
CH2
0.022
0.016
0.092
0.061
0.097
0.32
0.42
0.42
3.8
>50
>50
>50
>50
>50
>50
O
Substitution of the NH of the triazolone ring system led to only
modest increases in potency relative to the parent compounds 10
and 12 (Table 3). Analogs with basic piperidine side chains 39
and 40 had a deleterious affect on potency while modulating the
basicity of the piperidine15 as with 41 resulted in an increase in po-
tency relative to the parent 12. Neutralizing the basicity of the
piperidine with the methylcarbamate analog 42 returned full ki-
nase potency. These substituents served a dual purpose: first they
augmented the selectivity of inhibitor and secondly they mitigated
the Permeability-glycoprotein (P-gp) liability vide infra (Table 4). A
panel screen of 38 kinases revealed a modest erosion in the selec-
tivity of 12, but upon N-substitution of the triazolone the selectiv-
ity returned (12 vs 37).9 N-Substitution of 10 did not affect the
selectivity profile (10 vs 34 and 38).9 In addition to improving
the selectivity profile, N-substitution also appears to be necessary
for cellular activity in the human cortical neuronal amyloid-b
34
CH2
O
O
O
35b
N
36
37
O
O
0.10
0.15
1.4
>50
>50
>50
>50
N
0.054
0.093
0.99
38
39
40
CH2
O
0.029
0.16
0.28
0.097
0.53
2.0
0.70
4.5
>50
>5.0
na
>50
>50
na
N
NH
N
O
>5.0
CF3
41
42
O
O
0.036
0.024
0.17
0.90
0.36
na
na
N
N
O
O
0.058
>5.0
>50
neurotoxicity assay.9,16 Compound 38 has an EC50 of 12
whereas the EC50 of the parent compound 10 was >50 M despite
lM
a
Values are means of at least three experiments at 10 lM ATP concentration, see
l
Supplementary data for experimental details.
possessing nearly identical activities against JNK1–3 in the bio-
chemical assay. This result indicates that inhibitors of JNK2 and 3
are viable neuroprotective agents.
b
1:1 mixture of enantiomers.
In order for these inhibitors to be effective neuroprotective
agents, they must have the appropriate in vitro pharmacokinetic
parameters, most notably a high rate of permeability and low P-
gp efflux, to pass through the blood–brain barrier and enter into
the parenchyma of the brain. Illustrated in Table 4 are the
in vitro pharmacokinetic properties of selected analogs. The (tetra-
hydropyran-4-yl)amine 12 imparts a significant improvement to
the passive permeability as is evident when compared to the
Table 2
SAR of naphthyl substituentsa
H
N
N
R1
O
N
N
R2
24
NH
O
#
R1
R2
JNK3 IC50
(
lM)
JNK2 IC50
(lM)
JNK1 IC50
(lM)
ERK2 IC50
(
lM)
P38a IC50 (lM)
12
25
26
27
28
29
30
H
F
NH2
Br
H
H
H
H
H
F
NH2
Cl
0.085
0.070
0.95
0.25
0.19
5.3
0.78
0.38
0.57
0.15
1.8
0.74
1.7
4.2
>0.50
2.6
>50
>50
>50
>50
>50
>50
na
>50
>50
>50
>50
>50
>50
na
0.43
0.054
0.094
0.014
H
H
0.11
a
Values are means of at least three experiments at 10 lM ATP concentration, see Supplementary data for experimental details.

318
G. D. Probst et al. / Bioorg. Med. Chem. Lett. 21 (2011) 315–319
Table 4
tion. The tactic of targeting these residues for isoform selectivity
In vitro pharmacokinetic propertiesa
has been exploited previously with different templates.17 Similar
templates have not reported selectivity for the JNKs over the MAP-
Ks to the extent we have reported here.18 The distances between
the malleable sulfide side chain of the gatekeeper Met146 and
the bridgehead carbons of the naphthalene ring are 3.6 Å and
H
N
N
N
R1
X
N
N
3.7 Å suggesting a sulfur-p
stacking interaction is present.19
43
O
R2
In summary, we have developed a series of highly selective
JNK2 and JNK3 inhibitors. This selectivity originates from the naph-
thalene ring protruding deep into the selectivity pocket. Addition-
ally, these inhibitors exhibit auspicious in vitro CNS-like
pharmacokinetic properties. This amalgamated data suggests these
compounds are promising agents for neurodegenerative disorders.
#
X
R1 R2
JNK3 IC50 Papp
P-gp
efflux
ratio
Ox. Met.b
(m, h)
(lM)
(nm/s)
10
12
25
CH2
O
O
H
H
F
H
H
H
0.024
0.085
0.070
9
157
73
2.6
12
na
10, 57
72, 73
100, 88
O
35c
O
O
H
H
0.092
0.10
218
51
1.6
1.5
23, 27
12, 59
Acknowledgements
N
36
We would like to thank Michael P. Bova, Jennifer Marugg, Way-
man Chan, Danny Tam, Carla Ramos, R. Jeffrey Neitz, and Robert
Arslanian for their contributions to this work.
N
37
38
O
H
H
0.054
0.029
185
81
1.4
na
2, 40
48, 2
CH2
N
A. Supplementary data
a
See Supplementary data for experimental details.
Percent remaining after 30 min incubation with liver microsomes (m = mouse
b
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.11.010.
and h = human).
c
1:1 mixture of enantiomers.
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Figure 2. Compound 34 bound to JNK3 kinase (1.7 Å resolution). The aminopyr-
idine is depicted hydrogen bonding with the Met149 of the hinge while the
gatekeeper Met146 side chain is depicted interacting with the naphthalene ring via
a sulfur-p interaction. The PDB code is 3OY1.
cyclohexylamine analog 10. Also, this perturbation leads to im-
proved metabolic stability in a microsomal assay (10 vs 12). Fluo-
rination on the naphthalene ring at the 6-position, 25, improves
the metabolic stability as well. N-Substitution of the triazolone
ring ameliorates the P-gp efflux liability (12 vs 35–37). This impli-
cates the lone hydrogen bond donor on the triazolone as the egre-
gious moiety inducing the P-gp activity, especially since each
appendage bears a hydrogen bond acceptor. Also, N-substitution
improves the permeability of the cyclohexyl series.
A crystal structure of 34 bound to JNK3 reveals that the naph-
thalene ring juts deep into the selectivity pocket (Fig. 2). Other
MAPKs do not have the capacity to accommodate the naphthalene
ring in the selectivity pocket, thus accounting for the high degree
of selectivity for this scaffold within the MAPK family. The isoform
selectivity for JNK2 and JNK3 over JNK1 can be rationalized as well:
JNK1 has a bulky Ile106 residue in the selectivity pocket that will
not accommodate the naphthalene substituent, whereas JNK2
and JNK3 are less sterically encumbered with Leu144 at that loca-
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