Discovery of 1,3,4-oxidiazole scaffold compounds as inhibitors of superoxide dismutase expression

Article abstract of DOI:10.1016/j.bmcl.2014.01.078

The treatment of neurodegenerative diseases is difficult because of multiple etiologies and the interplay of genetics and environment as precipitating factors. In the case of amyotrophic lateral sclerosis (ALS), we have knowledge of a handful of genes that cause disease when mutated. However, drugs to counteract the effect of genetic mutations have not yet been found. One of the causative genes, Cu, Zn-superoxide dismutase (SOD1) is responsible for about 10-15% of the genetically linked autosomal dominant disease. Our rationale was that compounds that reduce expression of the mutant protein would be beneficial to slow onset and/or disease progression. We screened candidate compounds using a cell-based in vitro assay for those that reduce mutant SOD1 (G93A) protein expression. This led to the discovery of 2-[3-iodophenyl) methylsulfanyl]-5pyridin-4-yl-1,3,4-oxadiazole, a known protein kinase inhibitor that decreases G93A-SOD1 expression in vitro and in the brain and spinal cord in vivo. However, this compound has a biphasic dose response curve and a likely toxophore which limit its therapeutic window for chronic disease such as ALS. Therefore, we designed and tested a focused library of analogs for their ability to decrease SOD1 expression in vitro. This exercise resulted in the identification of a lead compound with improved drug-like characteristics and activity. Development of small molecules that reduce the expression of etiologically relevant toxic proteins is a strategy that may also be extended to familial ALS linked to gain of function mutations in other genes.

Full text of DOI:10.1016/j.bmcl.2014.01.078

Bioorganic & Medicinal Chemistry Letters 24 (2014) 1532–1537
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of 1,3,4-oxidiazole scaffold compounds as inhibitors
of superoxide dismutase expression
b,
Thomas J. Lukas a, , Gary E. Schiltz , Hasan Arrat d,à, Karl Scheidt b,c,§, Teepu Siddique d,–
⇑
a Department of Molecular Pharmacology & Biological Chemistry, Northwestern University, 303 E. Chicago Ave, Chicago, IL 60611, United States
b The Center for Molecular Innovation and Drug Discovery, Silverman Hall, Evanston, IL 60208, United States
c Department of Chemistry, The Center for Molecular Innovation and Drug Discovery, Silverman Hall, Evanston, IL 60208, United States
d Department of Neurology, Northwestern University, Chicago, IL 60611, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The treatment of neurodegenerative diseases is difficult because of multiple etiologies and the interplay
of genetics and environment as precipitating factors. In the case of amyotrophic lateral sclerosis (ALS), we
have knowledge of a handful of genes that cause disease when mutated. However, drugs to counteract
the effect of genetic mutations have not yet been found. One of the causative genes, Cu, Zn-superoxide
dismutase (SOD1) is responsible for about 10–15% of the genetically linked autosomal dominant disease.
Our rationale was that compounds that reduce expression of the mutant protein would be beneficial to
slow onset and/or disease progression. We screened candidate compounds using a cell-based in vitro
assay for those that reduce mutant SOD1 (G93A) protein expression. This led to the discovery of
2-[3-iodophenyl)methylsulfanyl]-5pyridin-4-yl-1,3,4-oxadiazole, a known protein kinase inhibitor that
decreases G93A-SOD1 expression in vitro and in the brain and spinal cord in vivo. However, this
compound has a biphasic dose response curve and a likely toxophore which limit its therapeutic window
for chronic disease such as ALS. Therefore, we designed and tested a focused library of analogs for their
ability to decrease SOD1 expression in vitro. This exercise resulted in the identification of a lead
compound with improved drug-like characteristics and activity. Development of small molecules that
reduce the expression of etiologically relevant toxic proteins is a strategy that may also be extended to
familial ALS linked to gain of function mutations in other genes.
Received 17 December 2013
Revised 25 January 2014
Accepted 28 January 2014
Available online 8 February 2014
Keywords:
Amyotrophic lateral sclerosis
Superoxide dismutase
Transgenic mouse
Inhibitor
Pharmacokinetics
Chemical synthesis
Hit-to-lead
Ó 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
Amyotrophic lateral sclerosis (ALS) is etiologically heteroge-
neous and in ten percent of cases the disease is inherited as a
dominant, recessive or X-linked dominant trait, (familial ALS or
FALS). The other 90 percent of cases have no identifiable history
of familial disease and are called sporadic ALS or SALS. We and
others have identified mutations in five genes that cause ALS.
Mutations in these genes, SOD1,1 TDP-43(TARBP),2,3 FUS,4,5
optineurin (OPTN),6 Ubiquilin 2 (UBQLN2),7 and C9ORF728,9 cause
the formation of aggregates in motor neurons of the spinal cord.
Of interest is the fact that TDP-43, FUS, optineurin, p-62 (SQSTM1),
and ubiquilin2 are also found in inclusions in the motor neurons of
SALS patients in the absence of mutations in the genes for these
proteins.7,10–12 Wild-type SOD1 has been reported to be present
within SALS cases with Lewy-body like inclusions13,14 and recent
reports using SOD1 aggregate specific antibodies have detected
aggregated SOD1 in SALS cases15,16 and in the cerebrospinal fluid
of some ALS patients.17 One path for induction of wild-type SOD1
aggregates is through deamidation of asparagines residues.18
There is genetic proof of principle in SOD1-linked ALS that onset
is directly influenced by the level of the mutant protein. Manipula-
tion of SOD1 expression by gene dosage,19 siRNA,20 and neuron
specific knockdown21 is directly correlated with disease onset
in vivo. Previous high-throughput screening of compound libraries
for compounds that reduce SOD1 expression in cultured cells
yielded compounds that were generally too toxic to use in animal
studies.22 Our current work describes the efforts of many years
leading to discovery of a new class of compounds that reduce
SOD1 expression in fibroblasts from transgenic mice expressing a
mutant SOD1 and exhibit favorable pharmacokinetics with respect
⇑
Corresponding author. Tel.: +1 312 503 0847; fax: +1 312 503 5349.
E-mail addresses: t-lukas@northwestern.edu (T.J. Lukas), ges480@northwestern.
edu (G.E. Schiltz),
harrat75@gmail.com (H. Arrat), Scheidt@northwestern.edu
(K. Scheidt), t-siddique@northwestern.edu (T. Siddique).
Tel.: +1 847 467 2287.
à
Tel.: +1 773 469 9621.
Tel.: +1 847 491 6659.
Tel.: +1 312 503 4737.
§
–
http://dx.doi.org/10.1016/j.bmcl.2014.01.078
0960-894X/Ó 2014 The Authors. Published by Elsevier Ltd.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

T. J. Lukas et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1532–1537
1533
Figure 1. Chemical structures of the commercially available compounds tested in the in vitro assays for their ability to inhibit SOD1.
Figure 2. Inhibition of SOD1 protein expression in fibroblasts from G93A-SOD1 mice. Fibroblasts were treated with the title compounds at the indicated concentration for
48 h. Cells were washed, lysed, and SOD1 levels measured by ELISA. SOD1 levels are normalized to the total protein in the lysate.

1534
T. J. Lukas et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1532–1537
to CNS distribution. Thus, we have discovered the first non-toxic
class of small molecules that may be useful for treating SOD1-FALS
and ALS where SOD1 may be involved.
pounds including some natural products. Figure 2 summarizes
the results from six of the commercially available compounds. (Cell
preparation and assay methods are in the Supplementary file). Two
compounds (Aloisine A and GSK3B-IX) increased SOD1 expression,
while several compounds inhibited at lower concentrations but
reversed at higher concentrations yielding a biphasic pattern.
Among these compounds, GSK3B-II was the most potent at inhib-
iting G93A-SOD1 expression (Fig. 3A). The IC50 values for GSK3b
kinase inhibition from the literature compared to SOD1 expression
are in shown in Table 1. GSK3B-VI also inhibits SOD1 expression
but this compound covalently modifies GSK3b kinase at the active
Small molecule inhibitors of SOD1 expression
Accumulated evidence suggests that inhibition of glycogen syn-
thase kinase III (GSK3b) might be beneficial to survival of the mu-
tant SOD1 transgenic mouse23–25 however, SOD1 levels were not
evaluated in those studies. Thus, we used cultured fibroblasts from
the G93A-SOD1 transgenic mouse to screen GSK3b protein kinase
inhibitors (Fig. 1) for their effects on SOD1 expression. The trans-
gene construct contains the human SOD1 promoter so that cellular
signaling processes that affect transcription of the gene will be
fully functional. We chose a structurally diverse group of com-
site26 and exhibits cell toxicity at concentrations greater than 5
lM
making it a poor therapeutic candidate. Kenpaullone, one of the
more potent GSK3b inhibitors (Table 1), only weakly decreased
SOD1 expression. Thus, the disconnect between potencies of
GSK3b inhibitors and their effect on SOD1 expression suggests that
inhibition of GSK3b may not be the primary mechanism for
decreasing G93A-SOD1 expression in cultured fibroblasts, although
other explanations such as differences in cell permeability cannot
be ruled out. We also determined that the decrease of SOD1
expression by GSK3B-II is primarily due to reducing the level of
SOD1 mRNA (Fig. 3B). Thus, GSK3B-II affects cellular processes that
lead to a decrease in the production of SOD1 mRNA and protein.
While GSK3B-II is a potentially useful molecular probe to study
the effects of reducing SOD1 expression, the compound exhibits a
biphasic dose–response curve and contains a potential toxophore
(Aryl-Iodo) which reduces its therapeutic potential. Hit-to-lead
medicinal chemistry was undertaken to quickly expand the SAR
and develop more drug-like inhibitors, especially ones without
the aryl iodide group. Modifications to previously reported condi-
tions27,28 were used to synthesize new 1,3,4-oxadiazole analogs
as shown in Scheme 1. Commercially available ethyl isonicotinate
was refluxed with hydrazine hydrate for 1 h at 60 °C and the
solvent was evaporated. Trituration of this solid with diethyl ether
afforded pure hydrazide 2 in 86% yield. The treatment of hydrazide
2 with CS2 and KOH in 60 °C for 18 h produced a solid upon con-
centration in vacuo. It was found that this material could be easily
purified by trituration with H2O followed by filtration to give thiol
3 in 78% yield, thus avoiding chromatography over the first two
steps. This operationally simple procedure afforded multi-gram
quantities of 3 for subsequence focused library synthesis. Finally,
diversification of the aryl ring was achieved by nucleophilic
displacement reaction of thiol 3 with substituted aryl bromides
in room temperature DMF using K2CO3 as base. The final com-
pounds (4) were produced in yields of between 24% and 74%
depending on the aromatic ring substituent. All final compounds
were judged to be consistent with desired product by 1H NMR
spectroscopy and had >95% purity as observed by liquid chroma-
tography–mass spectrometry analysis.
Figure 3. Inhibition of SOD1 protein and mRNA expression by GSK3B-II in G93A-
SOD1 mouse fibroblasts. (A) Dose-dependent changes in G93A-SOD1 protein
expression and (B) SOD1 mRNA (n = 3). Data are normalized to GAPDH activity
(protein) or mRNA. Error bars are SEM.
Structure–activity relationships (SAR) were developed using
mono aryl substituents on the benzyl ring (Table 2) to probe the
Table 1
Published GSK3b inhibitors and measured SOD1 expression
Cpd Name
GSK3b IC50 SOD1 IC50
Comments
(nM)
(nM)
1
2
3
4
5
6
7
GSK3B-IX
GSK3B-XI
5b
Increases SOD1 Also inhibits CDK5,CDK2, CDK1
25b
10,000
10,000
650
Also inhibits CDK4
Also inhibits CDK5,CDK2, CDK1
Covalent binding inhibitor
Kenpaullone 23c
GSK3B-VI
Aloisine
SB216763
GSK3B-II
1000d
650e
9f
Increases SOD1 Also inhibits CDK5, CDK1
3000
625
Active against GSK3B in vivog
390a
A
b
c
Ref. 35.
Product information datasheet (EMD, Calbiochem).
Ref. 36.
Ref. 26.
Ref. 37.
Ref. 38.
Refs. 39,40.
d
e
f
Scheme 1. Synthesis of 1,3,4-oxadiazole compounds. (a) hydrazine–H2O, EtOH,
reflux, 1 h; (b) CS2, KOH, EtOH, 60 °C, 18 h; (c) K2CO3, Aryl-Br, DMF, rt, 2 h.
g

T. J. Lukas et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1532–1537
1535
Table 2
Inhibition of SOD1 expression by 1,3,4-oxadiazoles
N
O
N
ID
ClogPa
Sigmab
Sigma+b
Relative SOD1 expression 10 l
M compound (p-value)c
R
S
N
7 (GSK3B-II)
NUCC-433
NUCC-319
NUCC-435
NUCC-439
NUCC-432
NUCC-318
NUCC-434
NUCC-440
NUCC-320
NUCC-321
NUCC-324
NUCC-436
NUCC-431
NUCC-441
R = 3-Iodo
R = 3-Methoxy
R = 3-Fluoro
2.91
1.71
1.93
2.82
2.51
1.53
2.65
1.71
2.51
2.65
2.91
1.93
2.29
1.53
2.29
0.352
ꢀ0.268
0.337
0.54
0.373
0.71
0.391
0.115
0.227
0.232
0.18
0.062
ꢀ0.17
0.778
NA
0.359
0.047
0.352
0.612
0.399
0.674
0.405
ꢀ0.778
0.114
0.15
0.73 (0.022)
0.50 (0.005)
1.43 (0.001)
1.57 (0.003)
0.96
R = 4-Trifluoromethyl
R = 3-Chloro
R = 3-Nitro
R = 3-Bromo
R = 4-Methoxy
R = 4-Chloro
R = 4-Bromo
R = 4-Iodo
1.17
0.91
0.47 (0.001)
1.23 (0.09)
1.03
0.69 (0.026)
0.86
1.26
1.02
1.33 (0.07)
0.135
ꢀ0.073
ꢀ0.311
0.79
R = 4-Fluoro
R = 4-Methyl
R = 4-Nitro
R = H
0
a
b
c
ClogP was calculated using ChemBioOffice-ChemDraw V13.
From Ref. 30.
If not shown.
requirements around this portion of the molecule. Aromatic ring
modifications were found to have a significant effect on the
compounds’ ability to reduce SOD1 expression. The two best com-
pounds had methoxy substituents at the 3-position (NUCC-433) or
4-position (NUCC-434) and significantly reduced the level of SOD1
expression to 47–50% of control at 10 lM. Some compounds such
as NUCC-319 (4-fluoro) and NUCC-435 (4-trifluromethyl) actually
showed a significant increase in SOD1 expression, confirming the
importance of the aryl ring in functional activity. The unsubstitut-
ed benzyl ring (NUCC-441) activates expression of SOD1 while
other substituents (chloro, nitro, bromo, methyl) at the 3 or 4 posi-
tion of the ring were comparable to control in SOD1 expression.
Interestingly, there is a trend where electron withdrawing substit-
uents tended to cause an increase in SOD1 expression (NUCC-319,
435, 432, 440), while electron donating groups tended to produce
the largest SOD1 reduction (NUCC-433 and 434). Dose–response
relationships were determined for NUCC-433 and 434 as shown
in Figure 4. Unlike GSK3B-II (Fig. 3A), both compounds exhibit a
flattened rather than upward curvature at higher concentration A
number of other analogs were synthesized and tested which had
variations in the pyridine portion of the molecule, including the
3-hydroxyl-, 3-amino-4-pyridyl, 3-pyridyl, and fused ring system
derivatives. All of these compounds with the exception of NUCC-
322 (3-pyridyl) showed either no effect on SOD1 expression or
slight increases.
Figure 4. Inhibition of SOD1 expression in mouse fibroblasts by NUCC-433 and
We sought to quantify compound behavior by Hansch
analysis29 using ClogP and the sigma or sigma+ values for meta
and para groups derived by Hammett.30 Sigma values are based
upon the ionization of substituted benzoic acids, while the sigma+
values are based upon the solvolysis of substituted 2-phenyl-2-
propyl chlorides.30 Three equations were tested for correlation of
the activity data with compound parameters.
NUCC-434. (A) Dose–response curve for NUCC-434 and (B) NUCC-433. Note the
decrease in upward curvature of both compounds at 10 lM. Error bars are SEM.
was to Eq. 1 and Eq. 2 (r2 = .55). The coefficients for Eq. 1 are:
1/relSOD1 = (ꢀ0.1667)ClogP + (ꢀ0.2331)sigma + (ꢀ0.4906))sigma+
+ 1.684. A plot of the predicted and experimental values is shown
in Figure. 5. The sole outlier was NUCC-436 based upon Grubbs test
(http://www.graphpad.com). Alternate analysis using Q values
(sum of squares of the residuals) gave comparable results.
One test of the specificity of the correlation was from testing of
NUCC-322 (Fig. 6), an isomer of the 4-bromo compound (NUCC-
320). While NUCC-320 showed no effect on SOD1 expression,
NUCC-322 inhibited SOD1 expression to 68.6% of control at
1=ðrelSOD1Þ ¼ C log P þ sigma þ sigmaþ
1=ðrelSOD1Þ ¼ C log P þ sigmaþ
1=ðrelSOD1Þ ¼ C log P þ sigma
ð1Þ
ð2Þ
ð3Þ
Using the ‘systemfit’31 package in R (http://www.R-project.org/)
the coefficients for the variables were calculated by solving simul-
taneous equations (Ordinary Least Squares). The best fit (r2 = 0.58)
10
lM (p = 0.015). This suggests that both ends of the structure
contribute to target binding. Relatedly, NUCC-437 and NUCC-438

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T. J. Lukas et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1532–1537
Table 3
Distribution of GSK3B-II in mouse tissues after a 20 mg/kg injection (n = 2)
Tissue
Time
Concentration (lM)
Brain
Spinal Cord
Serum
Brain
Spinal cord
Serum
1 h
1 h
1 h
24 h
24 h
24 h
0.944
4.00
0.672
0.077
0.855
0.073
Table 4
Distribution of CMIDD-434 in mouse tissues after a 10 mg/kg injection (n = 2)
Time (h)
Serum (
l
M)
Spinal cord (
lM)
Brain (lM)
Figure 5. Plot of predicted versus experimental data for the inhibition of SOD1
expression by 1,3,4-oxadiazole compounds .The linear regression line was calcu-
lated using GraphPad Prism.
2
4
24
0.153
0.334
0.123
0.057
0.162
0.113
0.029
0.047
ND*
*
ND = Not detected.
Figure 7. Inhibition of SOD1 protein expression in the G93A-SOD1 mouse. GSK3B-I
treatment was at 20 mg/kg IP every other day for 26 days. Mice were sacrificed and
SOD1 measured in the indicated tissues. The change in expression was significant
(
⁄ = p <0.05, ⁄⁄⁄ = p <0.001) in all tested tissues (n = 20). Error bars are SEM.
(Table 4). Such changes in distribution dynamics using cyclodex-
trins have not been studied in detail.
Figure 6. Structures of related 1,3,4-oxadiazole analogs.
As a proof of concept study, compound GSK3B-II was evaluated
in vivo for its ability to reduce levels of SOD1 in vivo. Initial testing
was carried out in a small cohort (5–6 animals) of G93A-SOD1 mice
(high level of mutant SOD1 expression). The drug was dosed at
20 mg/kg IP every other day for 26 days. Mice were sacrificed
and SOD1 was measured by ELISA. In all tissues sampled: spinal
cord, cerebellum, brain stem, and cerebral cortex, significant
decreases in SOD1 were measured (Fig. 7).
(Fig. 6) that have the benzyl group replaced by pyridyl exhibited
activity (at 10 lM) not significantly different from control indicat-
ing a target preference for benzyl groups.
The blood brain barrier permeability of GSK3B-II was deter-
mined in nontransgenic mice. At 20 mg/kg (intraperitoneal), the
compound rapidly distributes into the brain and spinal cord. This
compound is also long-lived in the CNS, with drug still detectable
after 24 h in the brain and spinal cord (Table 3). The peak and
sustained concentrations found in the spinal cord and brain indi-
cate that the 20 mg/kg dose puts the drug into the inhibitory range
found in the cellular assays.
We also tested compound NUCC-434 for distribution in non-
transgenic mice. However, the solubility of this compound was
poor in the standard 1–2% DMSO vehicle that we used for GSKB-
II. While there are a multitude of methods for improving aqueous
solubility of drugs32 we chose a relatively simple route using a
cyclodextrin based carrier (Sulfo-butylether beta-cyclodextrin,
Captisol) to solubilize the drug in aqueous solution. Using the cyclo-
dextrin carrier, we were able to solubilize NUCC-434 to 2 mg/mL in
water and deliver 10 mg/kg to nontransgenic mice for pharmacoki-
netics. Like GSK3B-II the compound entered the CNS and persisted
for 24 h in the spinal cord. However, the distribution dynamics are
different in the presence of the cyclodextrin which appears to slow
uptake into the CNS as the peak drug concentration was delayed
Conclusions
Compounds GSK3B-II, NUCC-433, and NUCC-434 are the first
small molecules to exhibit dose dependent reduction of SOD1
expression in vitro and in the G93A-SOD1 mouse in vivo (GSK3B-
II) Compared to antisense oligonucleotides33 and the APC analog,34
we found a comparable decrease of SOD1 protein in cultured cells
with the new 1,3,4-oxdiazole analogs reported here. Thus, these
and related compounds may offer an opportunity to develop a
small molecule based ALS therapy.
Acknowledgments
The authors thank Dr. Rongen Fu and Dr. Erdong Liu for mouse
colony maintenance and animal genotyping during the course of
the project. A part of this work was performed by the Northwestern

T. J. Lukas et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1532–1537
1537
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