Design and synthesis of a novel, orally active, brain penetrant, tri-substituted thiophene based JNK inhibitor

Article abstract of DOI:10.1016/j.bmcl.2011.01.046

The SAR of a series of tri-substituted thiophene JNK3 inhibitors is described. By optimizing both the N-aryl acetamide region of the inhibitor and the 4-position of the thiophene we obtained single digit nanomolar compounds, such as 47, which demonstrated an in vivo effect on JNK activity when dosed orally in our kainic acid mouse model as measured by phospho-c-jun reduction.

Full text of DOI:10.1016/j.bmcl.2011.01.046

Bioorganic & Medicinal Chemistry Letters 21 (2011) 1838–1843
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and synthesis of a novel, orally active, brain penetrant,
tri-substituted thiophene based JNK inhibitor
Simeon Bowers a, , Anh P. Truong a, , R. Jeffrey Neitz a, Martin Neitzel a, Gary D. Probst a, Roy K. Hom a,
Brian Peterson a, Robert A. Galemmo Jr. a, Andrei W. Konradi a, Hing L. Sham a, Gergley Tóth b, Hu Pan b,
Nanhua Yao b, Dean R. Artis b, Elizabeth F. Brigham c, Kevin P. Quinn d, John-Michael Sauer d, Kyle Powell e,
Lany Ruslim e, Zhao Ren e, Frédérique Bard e, Ted A. Yednock a,b,c,d,e, Irene Griswold-Prenner e
⇑
⇑
a Department of Chemical Sciences, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, United States
b Department of Molecular Design, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, United States
c Department of Pharmacology, Elan Pharmaceuticals, 800 Gateway 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:
The SAR of a series of tri-substituted thiophene JNK3 inhibitors is described. By optimizing both the
N-aryl acetamide region of the inhibitor and the 4-position of the thiophene we obtained single digit
nanomolar compounds, such as 47, which demonstrated an in vivo effect on JNK activity when dosed
orally in our kainic acid mouse model as measured by phospho-c-jun reduction.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 3 December 2010
Revised 11 January 2011
Accepted 12 January 2011
Available online 20 January 2011
Keywords:
c-Jun N-terminal kinases
JNK inhibitor
Neurodegeneration
Phospho-c-jun reduction
The c-Jun N-terminal kinases (JNKs) are serine/threonine protein
kinases in the mitogen-activated protein kinase (MAPK) family.1
The JNKs regulate signal transduction in response to stress stimuli
such as UV light, reactive oxygen species, cytokines, hypoxia and
protein misfolding.2 Three isoforms of JNK have been identified:
JNK1, JNK2 and JNK3.3 JNK1 and JNK2 are ubiquitously expressed
while JNK3 is localized primarily in the brain.4 JNK1 is suggested
to play a role in metabolic disorders such as type-2 diabetes1 while
JNK2 is involved in the pathology of autoimmune diseases such as
rheumatoid arthritis and asthma as well as vascular diseases and
atherosclerosis.1 JNK3 has been implicated in playing important
roles in models of neurodegeneration such as the synaptic loss
associated with Alzheimer’s disease, mediation of neurotoxicity in
Parkinson’s disease as well as involvement in Huntington’s disease,
and cerebral ischemia.5 JNK3 knockout mice are viable and when
treated with the neuroexcitotoxin kainic acid, they show decreased
neuronal death and seizure activity.6a In a separate study, JNK3
knockout mice showed reduced downstream c-Jun phosphoryla-
tion and reduced brain injury after cerebral ischemia-hypoxia
compared to wild-type animals.6b Taken together, these data imply
that inhibition of JNK3 may be neuroprotective.
For a JNK3 inhibitor to demonstrate in vivo neuroprotection it
must be brain penetrant and have high kinase selectivity to avoid
potential toxicity. While there are reports of selective JNK3 inhib-
itors,7 we focused on JNK inhibitors with selectivity over the clo-
sely related MAP kinases p38
a
and ERK2.1h Previously, we have
reported a class of thiophene based JNK inhibitors such as
compound 1 (Fig. 1) which displayed favorable permeability, low
P-gp efflux and selectivity for JNK over p38a
and ERK2.8 Reported
in this Letter are our efforts to improve the JNK3 potency of this
class of compounds while retaining their good selectivity and phar-
macokinetic properties.
μM
μM
μM
JNK3 IC50 = 2.2
JNK2 IC50 = 23
JNK1 IC50 = 1.6
O
S
S
N
H
α
μM
μM
p38 IC50 > 50
O
ERK2 IC50 > 50
O
μM
Hank's Buffered Salt Solution solubility = 72
MDR MDCK A>B = 144 nm/sec
P-gp efflux = 0.93
1
⇑
Corresponding authors.
E-mail addresses: simeon.bowers@elan.com (S. Bowers), anh.truong@elan.com
(A.P. Truong).
Figure 1. In vitro properties for compound 1.13,16
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.01.046

S. Bowers et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1838–1843
1839
Table 2
SAR of the aryl acetamide-4-methyl thiophene
O
S
Me
N
H
R
O
O
a
a
a
Compd
R
JNK3 IC50
(nM)
JNK1 IC50
(nM)
JNK2 IC50
(nM)
15
16
263
504
283
597
1838
N
O
3
4524
613
N
N
O
17
18
99
295
284
N
3
O
226
2571
N
3
Figure 2. Crystal structure of compound 1, in green, bound to JNK3 in the presence
of the JIP1 peptide (2.2 Å resolution). Compound 1 forms a hydrogen bond with
Met149 of the hinge while the gatekeeper residue, Met146, lies within proximity to
the inhibitor. The PBD deposition code is 3OXI. For experimental conditions see
Ref. 15.
H
N
19
20
1020
162
686
95
4150
765
N
The X-ray co-crystal structure of compound 1 is shown in Fig-
ure 2. The amide carbonyl of the inhibitor forms a hydrogen bond
with the NH of Met149 while the thiophene ring lies within 4 Å of
the gatekeeper residue Met146. This crystal structure revealed a
large pocket9 in the vicinity of Met146 and molecular modeling
suggested that it would be possible to prepare tri-substituted thio-
phenes and utilize the third substituent to explore a hydrophobic
interaction with the gatekeeper residue Met146.
N
21
110
55
409
N
22
23
62
31
78
863
703
N
N
O
O
S
125
S
R'
OR
a
R'
N
H
H2N
a
Values are means of at least three experiments at 10
Ref. 13.
lM ATP concentration. See
OR
O
O
OMe
CO2H
2
3
Br
a, b
Scheme 1. Reagents and conditions: (a) 4-MeOPhCH2CO2H, POCl3, pyridine, 0 °C,
5 min.
N
N
10
11
Table 1
SAR of the 4-position of the thiophene
Scheme 2. Reagents and conditions: (a) Pd2(dba)3, Q-Phos, (2-tert-butoxy-2-
oxoethyl)zinc(II) chloride, THF, rt to 50 °C; (b) HOAc, HCl, reflux.
O
S
R'
OR
N
H
O
3
CO2Me
a, b
N
CO2H
O
N
HO
12
12
13
OMe
a
a
a
Compd R0
R
JNK3 IC50
(
l
M) JNK1 IC50
(l
M) JNK2 IC50 (lM)
O
3
c, d
4
5
6
7
8
9
Me
Et
cPr
CF3
CN
Me
Me
Et
Et
Et
0.70
9.11
9.62
38.8
0.31
3.02
0.59
19.3
15.58
18.9
0.35
3.14
22.5
6.29
>50
0.93
28.4
CO2Me
N
CO2H
HO
14
CCH Et
1.05
Scheme 3. Reagents and conditions: (a) PPh3, DIAD, 2-(1H-imidazol-1-yl)propanol,
THF, 70%; (b) HOAc, HCl, reflux; (c) 1-chloro-3-iodopropane, K2CO3, CH3CN, 90 °C;
piperidine, NaI, CH3CN, 90 °C; (d) HOAc, HCl, reflux.
a
Values are means of at least three experiments at 10
Ref. 13.
lM ATP concentration. See

1840
S. Bowers et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1838–1843
Since the 4-methyl thiophene analog 4 gave an improvement in
potency, this region of the inhibitor was held constant while the
SAR of the acetamide region was explored (Table 2). From our pre-
vious report,8 we demonstrated that replacing the para-methoxy-
phenyl moiety with quinolines, isoquinolines and quinolinones
afforded compounds with improved potency. The quinoline, iso-
quinoline, and quinoxaline analogs were prepared via alpha-aryla-
O
S
O
S
S
Me
NH
Me
c
a, b
Me
N
N
H
H2N
H
R
R
NH2
OMe
O
N
O
N
R'
26
24
25
tion of
a bromoheterocycle in the presence of Q-phos and
Scheme 4. Reagents and conditions: (a) RCH2CO2H, POCl3, pyridine, 0 °C; (b) NH4Cl,
NH4OH (aq); (c) (i) for R0 = H dimethylformamide-dimethylacetal, for R0 = Me
dimethylacetamide-dimethylacetal; (ii) NH2NH2.
10
Pd2(dba)3 as shown in Scheme 2. Phenol analogs were also
prepared via a Mitsunobu reaction between phenol 12 and the
corresponding alcohol, or by alkylation of phenol 12 with the cor-
responding halo-alkyls (Scheme 3). After ester hydrolysis the
resulting acids were coupled with compound 2 as in Scheme 1 to
afford the analogs shown in Table 2.
Replacement of the para-methoxyphenyl group with 2-(4-(pyri-
din-4-yl)phenyl)acetamide gave a three-fold improvement in po-
tency against JNK3 (15 JNK3 IC50 = 263 nM compared to 4 JNK3
IC50 = 700 nM) (Table 2). The most potent compound in this series
was the 5-isoquinolyl analog 22 (JNK3 IC50 = 62 nM), with JNK3
A small series of analogs bearing substituents at the 4-position
of the thiophene were prepared in order to explore the interaction
of the inhibitor with the gatekeeper residue in JNK3. These analogs
were readily obtained by POCl3 mediated coupling of the amino
thiophenes 2 with 2-(4-methoxyphenyl)acetic acid (Scheme 1)
and the JNK inhibition data for these analogs is shown in Table 1.
This series of compounds indicated that small substituents such
as methyl (4 JNK3 IC50 = 700 nM) and cyano (8 JNK3 IC50 = 310 nM)
were well tolerated and gave the expected increase in activity
compared to disubstituted thiophenes such as 1. Larger substitu-
ents such as ethyl, cyclopropyl and trifluoromethyl resulted in a
dramatic reduction in potency and interestingly, the alkynyl analog
9 lost an order of magnitude of potency compared to nitrile 8.
Table 4
SAR of the 4-position of the thiophene
O
S
X
N
H
R
NH
N
N
Table 3
SAR of the aryl acetamide
Compd
R
X
JNK3
IC50
(nM)
JNK1
IC50
(nM)
JNK2
IC50
(nM)
p38
IC50
a
ERK2
IC50
(lM)
O
S
a
a
a
a
a
Me
NH
(lM)
N
H
R
N
N
N
N
O
O
O
43
44
45
46
47
48
Br
Cl
28
25
42
>20
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
N
R'
R0
Compd
R
JNK3 JNK1 JNK2 p38
a
IC50
M)
ERK2
IC50
(lM)
a
a
a
a
a
IC50
IC50
IC50
5
6
4
9
9
8
(nM) (nM) (nM)
(
l
27
28
Me 465
Me 324
331
226
824 na
na
>5
MeO
CN
Br
1300 >5
N
O
3
33
11
7
28
14
11
50
43
26
29
30
Me 197
Me 594
463
298
1620 >5
230 >5
>5
>5
N
N
N
N
N
N
Cl
CN
31
32
Me 80
45
81 >50
>50
>50
N
N
49
50
51
Br
Cl
34
18
42
15
12
90
42
41
>50
>50
>50
>50
>50
35.1
H
143
105
125 >50
N
N
N
N
N
O
O
33
34
Me 25
15
32
42 >50
31 >50
>50
>50
CN 12
H
25
a
a
Values are means of at least three experiments at 10
Ref. 13.
lM ATP concentration. See
Values are means of at least three experiments at 10
Ref. 13.
lM ATP concentration. See

S. Bowers et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1838–1843
1841
Table 5
amongst the more potent heterocyclic ester replacements and they
were therefore combined with the more potent tri-substituted
thiophenes. These analogs were prepared as shown in Scheme 4.
The commercially available amino thiophene 24 was acylated,
the ester converted into a primary amide and finally the primary
amide was converted into a 1,2,4-triazole in a two-step procedure
involving treatment with DMF–DMA followed by reaction with
hydrazine. In this series of analogs the C-methyl triazoles were
generally more potent than the monosubstituted triazoles and
the biaryl 28 and phenoxy acetamides 27 and 29 proved to be less
potent than the fused bicyclic acetamides such as quinoline 31 and
dihydroquinolinone 33 (Table 3). All future work focused on the
development of these analogs. These triazoles had similar potency
for JNK1 compared to JNK3, moderate selectivity over JNK2 and
In vitro metabolism, permeability and P-gp efflux data for select compounds
O
S
R'
NH
N
H
R
N
N
b
Compd
R
R0
JNK3
OxMet%b
(m, h)
Papp
P-gp
IC50
(nm/s)
effluxb
a
(nM)
N
N
N
O
O
O
34
44
45
Me
Cl
25
0, 0
148
3.2
0.9
4.1
excellent selectivity over the similar kinases p38a and ERK2.
5
6
0, 20
37, 39
233
With an optimized left-hand portion of the inhibitor and the tri-
azole as an effective ester replacement the SAR of the 4-position of
the thiophene was fine-tuned. It was reasoned that the methyl thi-
ophene would be a metabolic liability (see Table 5 and discussion
below) and therefore the methyl group was replaced with small
electron withdrawing substituents such as halogens and nitriles.
These analogs were prepared as shown in Scheme 5. Thiophene
38 was prepared by reaction of isothiocyanate 35 with ester 36 fol-
lowed by treatment of the resulting intermediate 37 with POBr3.12
Aminothiophene 38 was acylated to give 39 which was treated
with either copper chloride or copper cyanide followed by elabora-
tion of the methyl ester into the C-linked triazole via primary
amide 41 to give the analogs shown in Table 4.
The bromothiophenes were generally less potent against JNK3
compared to the chloro and cyano thiophenes which were essen-
tially equipotent (Table 4). Consistent with previous analogs, the
dihydroquinolinones tended to be the more potent analogs with
both compounds 44 and 45 displaying single digit nanomolar
JNK3 inhibition (JNK3 IC50 = 5 and 6 nM, respectively). To our de-
light no compounds in this series had a measurable IC50 against
CN
180
32
Me 143
1, 46
161
1.9
N
47
48
Cl
11
7
29, 50
48, 62
270
133
1.6
4.6
N
N
CN
a
Values are means of at least three experiments at 10
Ref. 13.
lM ATP concentration. See
b
See Ref. 16.
p38
a or ERK2 at the concentrations tested. In order to determine
activity approximately one order of magnitude better than the par-
ent para-methoxylphenyl analog 4 (JNK3 IC50 = 700 nM).
the broader kinase selectivity of the thiophene based inhibitors,
compound 47 was subjected to a screen of 38 kinases. This screen
revealed an exceptionally clean profile with only TTK being inhib-
As we have previously reported,8,11 it was possible to replace
the metabolically labile methyl ester with a heterocycle to obtain
compounds which were both more potent and stable than the
esters. In particular, it was found that C-linked 1,2,4-triazoles were
ited at greater than 50% at 10 l
M compound concentration.14
The crystal structure of JNK3 in complex with compound 34 in
the presence of JIP1 peptide was determined to 2.4 Å resolution as
O
O
S
a
b, c
O
C
FmocN
S
Cl
MeO
FmocHN
OMe
O
35
36
37
O
S
O
S
S
Br
Br
OMe
X
d
e
N
H
N
H
H2N
R
X
R
OMe
OMe
O
O
O
38
39
40
O
S
O
S
g
X
f
N
H
N
H
R
R
NH2
NH
O
N
N
41
42
Scheme 5. Reagents and conditions: (a) NaH, hexanes; (b) POBr3, toluene, reflux; (c) morpholine, CH2Cl2, rt; (d) RCH2CO2H, POCl3, pyridine, 0 °C; (e) CuX, DMF, 120 °C; (f)
NH4Cl, NH4OH (aq); (g) (i) DMF–DMA; (ii) NH2NH2.

1842
S. Bowers et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1838–1843
Figure 3. Crystal structure of compound 34 in green bound to JNK3 (2.4 Å resolution). The PBD deposition code is 3PTG. For experimental conditions see Ref. 15.
mentioned, the 4-methylthiophenes had poor metabolic stability
but replacement of the methyl group with a halogen or a nitrile re-
sulted in improved stability. In particular, the combination of the
**
6
isoquinoline acetamide with the cyanothiophene (48) provided
the greatest stability. Permeability was generally high for this ser-
ies of compounds but, unfortunately, the most metabolically stable
cyanothiophenes (45 and 48) exhibited unacceptable P-gp efflux in
MDR-MDCK cells.
5
4
3
2
1
0
Compound 47 exhibited the most favorable combination of po-
tency, metabolic stability, permeability and P-gp efflux and was
chosen to be dosed in our kainic acid mouse model. Kainic acid is
a potent agonist of a subtype of ionotropic glutamate receptor17a
and has been shown to induce the activation of MAPK family
kinases such as JNK.17b The effect of JNK inhibition was tested in
kainic acid-treated mice by quantitating the levels of phospho-c-
jun in brain tissue as a measure of JNK activity. Pretreatment with
a single, oral dose of compound 47 at 300 mg/kg resulted in a
significant 51% reduction of phospho-c-jun in the hippocampus
of FVB mice 4 h after an intraperitoneal injection of 25 mg/kg
kainic acid (Fig. 4)18 thus demonstrating the in vivo effect on JNK
activity of our inhibitors.
In conclusion, we have expanded the SAR of our thiophene
based JNK inhibitors. By optimizing both the arylacetamide region
of the inhibitor and the 4-position of the thiophene we obtained
single digit nanomolar compounds which, when dosed orally, dem-
onstrated a robust in vivo effect on JNK activity as measured by
phospho-c-jun reduction in our kainic acid mouse model. Further
optimization of these inhibitors to improve their pharmacokinetic
properties will be reported in due course.
Vehicle
Vehicle
Compound 47
300 mg/kg, PO
Kainic Acid
Figure 4. Effect of 47 (300 mg/kg) on phospho-c-jun levels in kainic acid (25 mg/
kg) treated mice. ⁄⁄p >0.01 significantly different by unpaired t-test with Welch
correction.
shown in Figure 3. This structure revealed the critical hydrogen
bond between the NH of Met149 and the carbonyl of the inhibitor
(Fig. 3). The triazole is in plane with the thiophene ring revealing
an internal hydrogen bond between the amide NH and the nitrogen
of the triazole. The fused bicyclic ring points toward solvent with
the carbonyl of the dihydroquinolinone engaged in a hydrogen
bond with a water molecule. The methyl at the 4-position of the
thiophene lies within proximity to the gatekeeper residue
(Met146) and explains why the larger substituents explored in this
region were not tolerated (Table 1).
Acknowledgments
We would like to thank Jennifer Sealy, Robert Galemmo, Jacek
Jagodzinski, David Quincy, Jing Wu, Michael Dappen, Lee Latimer,
Ferdie Soriano, Pam Santiago, David Chan, Grace Kwong, Ruth
The in vitro metabolism, permeability and P-gp efflux for a se-
lected number of inhibitors are shown in Table 5. As previously

S. Bowers et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1838–1843
1843
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Motter, Wes Zmolek, Ann Qin, Karina Wong, Danny Tam, and Mi-
chael P. Bova for their contributions to this work. We are also
grateful to DeCode Biostructures, Bainbridge Island, WA, USA for
the solution of the co-crystal structure of JNK3, JIP1, and inhibitors
1 and 34.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.01.046.
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