Novel aryl and heteroaryl substituted N-[3-(4-phenylpiperazin-1-yl)propyl]-1,2,4-oxadiazole-5-carboxamides as selective GSK-3 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2007.11.121

Synthesis, biological evaluation, and SAR dependencies for a series of novel aryl and heteroaryl substituted N-[3-(4-phenylpiperazin-1-yl)propyl]-1,2,4-oxadiazole-5-carboxamide inhibitors of GSK-3β kinase are described. The inhibitory activity of the synthesized compounds is highly dependent on the character of substituents in the phenyl ring and the nature of terminal heterocyclic fragment of the core molecular scaffold. The most potent compounds from this series contain 3,4-di-methyl or 2-methoxy substituents within the phenyl ring and 3-pyridine fragment connected to the 1,2,4-oxadiazole heterocycle. These compounds selectively inhibit GSK-3β kinase with IC₅₀ value of 0.35 and 0.41 μM, respectively.

Full text of DOI:10.1016/j.bmcl.2007.11.121

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 3661–3666
Novel aryl and heteroaryl substituted N-[3-(4-phenylpiperazin-
1-yl)propyl]-1,2,4-oxadiazole-5-carboxamides
as selective GSK-3 inhibitors
Angela G. Koryakova,a Yan A. Ivanenkov,b Elena A. Ryzhova,a Elena A. Bulanova,a
Ruben N. Karapetian,a Olga V. Mikitas,a Eugeny A. Katrukha,a
Vasily I. Kazey,a Ilya Okun,b Dmitry V. Kravchenko,a Yan V. Lavrovsky,a
Oleg M. Korzinova and Alexandre V. Ivachtchenkob,*
aDepartment of Organic Chemistry, Chemical Diversity Research Institute, 114401 Khimki, Moscow Reg., Russia
bChemDiv, Inc., Department of Organic, Biological and Medicinal Chemistry,
11558 Sorrento Valley Rd., San Diego 92121, CA, USA
Received 2 October 2007; revised 29 November 2007; accepted 30 November 2007
Available online 5 December 2007
Abstract—Synthesis, biological evaluation, and SAR dependencies for a series of novel aryl and heteroaryl substituted N-[3-(4-phen-
ylpiperazin-1-yl)propyl]-1,2,4-oxadiazole-5-carboxamide inhibitors of GSK-3b kinase are described. The inhibitory activity of the
synthesized compounds is highly dependent on the character of substituents in the phenyl ring and the nature of terminal hetero-
cyclic fragment of the core molecular scaffold. The most potent compounds from this series contain 3,4-di-methyl or 2-methoxy sub-
stituents within the phenyl ring and 3-pyridine fragment connected to the 1,2,4-oxadiazole heterocycle. These compounds selectively
inhibit GSK-3b kinase with IC50 value of 0.35 and 0.41 lM, respectively.
Ó 2007 Elsevier Ltd. All rights reserved.
Glycogen synthase kinase 3 (GSK-3) is a serine/threo-
nine kinase that has captured a great attention in mod-
ern drug discovery.1 At least three closely related
isoforms of GSK-3 kinase (GSK-3a, GSK-3b, and
GSK-3b2) play a major role in Hedgehog and Wnt
signaling pathways, regulate cellular mitosis, stem-cell
renewal and differentiation, cellular growth, motility
and apoptosis, circadian rhythm, transcription, insulin-
dependent glycogen synthesis, etc.2–7 Aberrant regula-
tion of GSK-3 kinases has been implicated in a range
of human pathologies including Alzheimer’s disease,
non-insulin-dependent diabetes mellitus (NIDDM) as
well as cancer and inflammatory disorders.5,8 It has be-
come clear that regulation of GSK-3 activity and the
therapeutic potential of small molecule GSK-3 inhibi-
tors constitute the key areas of investigation in the
broader realm of medicinal chemistry. At the present
day more than 40 inhibitors of GSK-3 kinases have been
identified.9–21 However, there are strong evidences high-
lighting the significant cell toxicity, various side-effects,
poor absorption, distribution, metabolism, and excre-
tion of these inhibitors which essentially restricted their
clinical application.
Aryl and heteroaryl substituted 1,2,4-oxadiazole-5-car-
boxamides represent a relatively little explored class of
heterocyclic structures with promising physiological
activities. Thus, they were recently reported as antiplate-
let, antithrombotic agents and partial serotonin antago-
nists.22 Several 1,2,4-oxadiazole- and 1,3,4-oxadiazole-
carboxamides containing different lipophilic moieties
(i.e., 4-biphenyl-, 1-naphthyl, phenylpropyl-, and n-hex-
yl substituents) and additional basic groups which are
mainly alkyl- and aminoalkyl residues have been re-
cently described as antiplatelet and antithrombotic com-
bounds as well as serotonin antagonists.23
In this paper, we describe a synthesis and biological
evaluation for a series of novel nonpeptide small
molecule inhibitors of GSK-3b kinase having general
formula I (Fig. 1). Structures containing this core frag-
Keywords: Oxadiazole-5-carboxamide; GSK-3b; Inhibitor; Kinase; C-
ombinatorial chemistry; Library.
*
Corresponding author. Tel.: +1 858 794 4860; fax: +1 858 794
4931; e-mail: av@chemdiv.com
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.11.121

3662
A. G. Koryakova et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3661–3666
O
R3
R2
N
R1
N
N
O
N
H
O
O
N
N
O
R
I
O
R4
R=Me, Pr
II
R1= substituted phenyl
R2= pyridyl, pyrimidyl, benzodioxolyl
R3, R4=H,Me
Cl
Cl
Cl
N
N
OH
OH
N
IV
O
N
Cl
H
H
III
N
N
O
NH
NH2
N
H
N
Figure 1. Developed compounds I and known GSK-3b inhibitors II–IV.
ment represent closely related bioisosteric/topological
analogues of known inhibitors of GSK-3b kinase (Struc-
tures II–IV)24,25 and can reasonably be regarded as po-
tential therapeutic agents targeted for the treatment of
several cognition and neurodegenerative disorders
including Alzheimer’s disease.
According to the mentioned approach, commercially
available nitriles 1a–e were reacted with hydroxyamine
in EtOH/H2O in the presence of NaHCO3 to give the
corresponding amidoximes 2a–e in good yields. The lat-
ter were dissolved in CHCl3 and then refluxed for 5 h in
pyridine with ethyl chloroxalate to furnish 3-heteroaryl
substituted ethyl 1,2,4-oxadiazole-5-carboxylates 3a–e.
The obtained esters were then easily converted into the
desired heterocyclic compounds 5{1–100} (yield 45–
85%) by reaction with N-aryl substituted 3-piperazin-
1-ylpropan-1-amines 4a–t (Fig. 2).
Our versatile synthesis of target compounds was accom-
plished according to a sequence of reactions shown in
Scheme 1. The applied strategy was based on previously
reported methods describing several synthetic routes to
3-substituted ethyl 1,2,4-oxadiazole-5-carboxylates and
their carboxamide analogues.26–28 For example, Santilli
and Morris have described a convenient synthesis of
3-[(phenylsulfonyl)methyl]-1,2,4-oxadiazole-5-alkylcarbox-
amides.26 In accordance with this approach, a series of
heterocyclic compounds containing this core fragment
was obtained by the reaction of initial alkyl and halogen
There are several high throughput- and cell-based bio-
logical assays performed for GSK-3b inhibitors.29–31
For example, for screening against GSK-3b kinase Baki
et al have recently reported a high throughput lumines-
cent assay based on the Kinase-Glo system.29 Cell-based
assay describing the ability of Sfrp-1 and Sfrp-2 pro-
teins, attenuators of Wnt signaling pathway, to inhibit
the accumulation of b-catenin in LiCl-treated cells has
also been reported.30 In our work all synthesized com-
pounds 5{1–100} were tested for their potency to inhibit
GSK-3b catalyzed proteolytic breakdown of its syn-
thetic glycogen-synthase-derived substrate peptide
substituted
2-[(phenylsulfonyl)methyl]imidamide-N0-
oximes with ethyl chloroxalate followed by the reaction
with various aliphatic amines. Unfortunately, 3-hetero-
aryl substituted 1,2,4-oxadiazole-5-alkylcarboxamides
containing N-arylpiperazin fragment have not been de-
scribed previously in scientific papers.
O
R1
N
OEt
Cl
HO
R1
N
N
O
NH2OH
O
N
1
Py/CHCl3
54-81%
NaHCO3
O
3a-e
R
NH2
2a-e
OEt
1a-e
55-85%
R1
N
1a-e:
a: 3-pyridyl
b: 4-pyridyl
c: 4-pyrimidyl
d: 5-pyrimidyl
N
R2-NH2 4a-t
O
45-85%
O
HN
e: 5-benzodioxolyl
R2
5
{1-100}
Scheme 1.

A. G. Koryakova et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3661–3666
3663
OMe
Me
N
N
N
NH2
NH2
Me
NH2
N
NH2
Me
Me
Me
N
N
N
N
Me
4d
4a
4c
4b
Me
Me
Me
N
N
N
N
N
NH2
NH2
NH2
NH2
Me
N
N
N
N
N
4h
4l
4e
4g
4k
4f
Me
N
NH2
N
N
N
NH2
Me
NH2
NH2
Cl
Me
N
N
N
N
4i
4j
Me
Me
Me
F
Me
Me
Me
N
N
N
NH2
NH2
NH2
NH2
N
N
N
4p
4m
4n
4o
Me
Cl
Me
NH2
N
N
NH2
Me
N
NH2
N
NH2
N
N
N
N
4t
4r
4q
4s
Me
Figure 2. Amines used in this work.
(GSM) in enzymatic ADP Hunter assay and cellular le-
vel of b-catenin measured by traditional ELISA proce-
dure in RKO cell-based assay (See Supporting
Information). Among the tested compounds, several
pyridine and pyrimidine substituted N-[3-(4-phenylpi-
perazin-1-yl)propyl]-1,2,4-oxadiazole-5-carboxamides dis-
played a moderate to high inhibitory activity in these
in vitro kinase assays (Tables 1 and 2). Other compounds
from this series have shown insignificant or exhibited no
detectable activity except several minor cases.
experiments have indicated a higher potency of 3,5-
pyrimidine derivatives 5{16–21} in contrast to their bio-
isosteric analogues containing 2,4- and 2,6-pyrimidine
fragments in enzymatic assay, whole pyrimidine series
exhibited no detectable activity against GSK-3b kinase
in the RKO cell-based assay. Unfortunately, several
other isosteric modifications of substituents in the
pyrimidine ring of tested compounds as well as classical
bioisosteric transformation of 1,2,4-oxadiazole into the
1,3,4-oxadiazole resulted in unacceptable loss of their
activity. Notable, although the replacement of the phe-
nyl group connected to the nitrogen atom of piperazine
moiety by benzyl fragment has also led to complete loss
of activity, bioisosteric transformation of pyridine het-
erocycle by 1,3-benzodioxole in 2-methyl-benzyl substi-
tuted derivative resulted in clarification of activity up
to IC50 = 0.64 lM. However, the inhibition was insuffi-
cient because 70% of kinase activity was kept even at
10 lM concentration of the tested compound. Addition-
ally, the replacement of the piperazine cycle by diaze-
pam had a disastrous effect on inhibitory activity.
Therefore, it can be tentatively suggested that location
of heteroatoms within pyridine and oxadiazole rings as
well as character of substitution in the aromatic frag-
ment play an essential role in activity of the studied
compounds. In accordance with this suggestion, we have
observed a clear correlation between the inhibitory abil-
ity and mentioned structural features (see Supporting
Information).
The most active compounds within pyridine substituted
series have a single methyl/methoxy or two methyl
substituents in the phenyl ring. These include dimethyl-
phenyl-piperazines 5{1} and 5{3}, methoxyphenyl-
piperazine 5{2}, and methylphenyl-methylpiperazine
5{4} derivatives (Table 1). These compounds have been
shown to have a relatively high activity in the enzymatic
ADP hunter assay (IC50 = 0.35–0.69 lM) and moderate
activity in the RKO Cell-based assay (IC50 = 16–
23 lM). It was disclosed that compounds 5{23} and
5{24} which contain 4-pyridine fragment were at least
in two times less active than compounds 5{1–15}, except
compound 5{22} which displayed comparable potency
to 5{11–15}. Furthermore, these agents were found to
partially inhibit GSK-3b kinase activity in enzymatic
ADP Hunter assay. In the same way as compounds
5{23–24}, a relatively weak potency has also been dem-
onstrated for pyrimidine derivatives 5{16–21} as com-
pared to 3-pyridine containing compounds 5{1–15}.
Among the tested compounds, only four pyridine deriv-
atives were shown to have moderate activity against
GSK-3b in cell-based assay (Table 2). Although further
To investigate the possible mechanism of action of the
tested compounds on GSK-3b kinase, the kinetic evalua-
tion was performed using various concentrations of an

3664
A. G. Koryakova et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3661–3666
Table 1. In vitro GSK-3b inhibitory potency of pyridine and pyrimidine substituted N-[3-(4-phenylpiperazin-1-yl)propyl]-1,2,4-oxadiazole-5-
carboxamides 5{1–24} in the enzymatic ADP Hunter assay
Y
X
R2
R1
z
R3
N
N
H
N
N
N
O
R4
O
5
{1-24}
R1
R2
R3
R4
X
Y
Z
IC50 (lM)
a
Compound
5{1}
5{2}
3-Me
2-OMe
2-Me
3-Me
2-Me
3-Me
H
4-Me
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
N
N
N
N
N
N
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
C
0.35 0.07
0.41 0.07
0.63 0.1
5{3}
5{4}
3-Me
H
0.69 0.1
5{5}
5{6}
H
0.71 0.15
0.71 0.15
0.86 0.18
0.86 0.17
0.89 0.18
0.9 0.16 (partial)
1.06 0.21
1.33 0.22
1.43 0.22
1.48 0.23
H
5{7}
5{8}
H
3-Me
3-Cl
6-Me
H
5{9}
5{10}
5{11}
5{12}
5{13}
5{14}
5{15}
5{16}
5{17}
5{18}
5{19}
5{20}
5{21}
5{22}
5{23}
5{24}
3-Me
3-Me
4-Me
2-Me
2-F
5-Me
H
H
4-Me
H
2-Me
3-Me
2-F
5-Cl
H
2
0.26 (partial)
2.61 0.27
2.99 0.3
H
2-Me
2-Me
2-Me
3-Me
3-Me
3-Cl
4-Me
5-Me
5-Cl
4-Me
H
3
0.3
3.38 0.31
3.48 0.31
3.5 0.32
1.13 0.06
4.0 0.6 (partial)
H
C
H
H
C
5
0.9
a ATP and GSM concentrations were kept at 100 lM and 50 lM, respectively.
Table 2. In vitro GSK-3b inhibitory potency of compounds which
exhibit activity in the RKO cell-based assay
increasing concentration of ATP or the peptide sub-
strate in the presence of different concentrations of the
inhibitor. Transformation of the data in the Linewe-
aver–Burke coordinates revealed an ATP-competitive
type of inhibition (Fig. 4).
Compound
IC50 (lM)
5{1}
5{2}
5{4}
5{6}
5{22}
16
23
17
2
4
3
19.15
>50
4
As reported in recent studies, the majority of GSK-3
inhibitors are not only acting against GSK-3, but are also
affecting many other structurally unrelated kinases. In
addition, because of high similarity in amino acid se-
quence between GSK-3a (51 kDa) and GSK-3b
(47 kDa) isoforms, it is difficult to identify an inhibitor
that can be selective against GSK-3a or GSK-3b. In spite
of this obstacle, previous immunoblot and biological as-
says revealed that several small molecule agents inhibit
selectively the activation of GSK-3b kinase. For example,
AR-A014418, a selective GSK-3b inhibitor, prevents the
expression of cell-cycle proteins.32 Notable, as reported
in some recent publications, selective inhibition of
GSK-3 activity had no effect on cell viability and/or apop-
tosis in several biological systems.33
exemplified compound 5{4}. In the enzymatic ADP Hun-
ter assay the competitive character of inhibition has been
demonstrated in the experiments, in which the inhibitory
potency was measured in response to increasing concen-
tration of ATP or the peptide substrate up to saturating
the enzyme level. The incremental increase in ATP con-
centration shifted the inhibition curves to the right as
one expected for competitive inhibition (Fig. 3). IC50 va-
lue of compound 5{4} varied from 0.2 to 2.5 lM depend-
ending on ATP concentration and not depend on
concentration of the peptide substrate.
Also, the competitive character of inhibition has been
demonstrated in the experiments, in which the GSK-
3b activity was measured in response to a stepwise
Selectivity of the most active compounds 5{1,2} and
5{4} within this series was primarily estimated in the

A. G. Koryakova et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3661–3666
3665
reactions with a panel of active recombinant human
protein kinases and the specific substrates for each indi-
vidual enzyme. These include a set of 4 serine/threonine
(Aurora A, Aurora B, Pim-1, NUAK1) and 4 tyrosine
(JAK2, IGF1R, EphB4, c-Met) kinases, phylogeneti-
cally and structurally unrelated to GSK-3b. The activity
of eight selected kinases was evaluated in the presence of
10 lM of tested compounds. It has been shown that
these agents exhibited a weak inhibition activity against
Pim-1 and no detectable inhibition toward other classes
of kinases. Thus, compound 5{2} was the most potent
inhibitor of Pim-1 kinase (IC50 = 8 lM), but the inhibi-
tion was partial and required higher concentrations of
the tested compound. Therefore, it can be strongly sug-
gested that examined compounds are selective inhibitors
of GSK-3b. Selectivity of the most active compounds
from this series is currently being evaluated against the
additional subset of kinases including CDKs, PKCa/c,
PDK, Akt, etc.
In summary, we synthesized a library of novel N-[3-(4-
phenylpiperazin-1-yl)propyl]-1,2,4-oxadiazole-5-carbox-
amides and tested them in a series of biological experi-
ments. Most of the obtained compounds are efficient
GSK-3b inhibitors. Compounds 5{1} and 5{2} with
3,4-di-methyl and 2-metoxy substituents in aromatic
ring are the most potent compounds from this series
(IC50 = 0.35 and 0.41 lM, respectively). Our primary
data suggest ATP-competitive character of GSK-3b
inhibition. The selected compounds 5{1–4} showed a
high selectivity against GSK-3b. Further biological
studies are continuing.
Acknowledgments
Figure 3. Effect of compound 5{4} on GSK-3b activity. The kinase
activity was assayed in the presence of indicated concentrations of
ATP and GSM peptide substrate. When ATP concentration was
varied, GSM was kept constant at 500 lM and vice versa.
The authors thank Dr. Konstantin V. Balakin and Dr.
Yan A. Ivanenkov (Department of Computational
Medicinal Chemistry, ChemDiv, Inc.) for SAR analysis
and preparation of manuscript.
Supplementary data
The rigorous experimental section and analytical data
for intermediates and final products (1H NMR, 13C
NMR, HRMS), experimental procedures for the biolog-
ical tests, inhibition kinetics and selectivity data for
compounds 5{1–4}, and data concerning the effect of
substituents in the phenyl ring and the key role of termi-
nal heterocyclic systems on the GSK-3b inhibitory activ-
ity are available free of charge via Internet at
www.elsevier.com. Supplementary data associated with
this article can be found, in the online version, at
doi:10.1016/j.bmcl.2007.11.121.
References and notes
Figure 4. Lineweaver-Burke transformation of the ATP concentration
curve for GSK-3b kinase at different concentrations of compound
5{4}. The plot demonstrates competitive character of inhibition, as the
inhibitor increased Km without affecting the apparent Vmax. GSM
concentration was kept constant at 500 lM.
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