Synthesis and biological evaluation of novel bis-aromatic amides as novel PTP1B inhibitors

Article abstract of DOI:10.1016/j.bmcl.2014.03.015

A series of bis-aromatic amides was designed, synthesized, and evaluated as a new class of inhibitors with IC₅₀ values in the micromolar range against protein tyrosine phosphatase 1B (PTP1B). Among them, compound 15 displayed an IC₅₀ value of 2.34 ± 0.08 μM with 5-fold preference over TCPTP. More importantly, the treatment of CHO/HIR cells with compound 15 resulted in increased phosphorylation of insulin receptor (IR), which suggested extensive cellular activity of compound 15. These results provided novel lead compounds for the design of inhibitors of PTP1B as well as other PTPs.

Full text of DOI:10.1016/j.bmcl.2014.03.015

Bioorganic & Medicinal Chemistry Letters 24 (2014) 1889–1894
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of novel bis-aromatic amides
as novel PTP1B inhibitors
Wen-Long Wang a,b, , , Chao Huang a, , Li-Xin Gao b, , Chun-Lan Tang b, Jun-Qing Wang a, Min-Chen Wu a,
⇑
Li Sheng b, Hai-Jun Chen b, Fa-Jun Nan b, Jing-Ya Li b, Jia Li b, , Bainian Feng a,c,
⇑
⇑
a School of Pharmaceutical Science, Jiangnan University, Wuxi 214122, China
b State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
c Jiangsu Alpha Biopharmaceuticals, Inc., Wuxi 214122, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of bis-aromatic amides was designed, synthesized, and evaluated as a new class of inhibitors
with IC50 values in the micromolar range against protein tyrosine phosphatase 1B (PTP1B). Among them,
compound 15 displayed an IC50 value of 2.34 0.08 lM with 5-fold preference over TCPTP. More impor-
tantly, the treatment of CHO/HIR cells with compound 15 resulted in increased phosphorylation of insu-
lin receptor (IR), which suggested extensive cellular activity of compound 15. These results provided
novel lead compounds for the design of inhibitors of PTP1B as well as other PTPs.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 6 February 2014
Revised 5 March 2014
Accepted 7 March 2014
Available online 15 March 2014
Keywords:
Bis-aromatic amides
PTP1B inhibitors
Selectivity
Cellular activity
Structure–activity relationships (SARs)
Reversible protein tyrosine phosphorylation, catalyzed by the
opposing actions of protein tyrosine kinases (PTKs) and protein
tyrosine phosphatases (PTPs), is considered the key pathway for
controlling protein functions in living cells.1 Dysregulation of pro-
tein tyrosine kinases (PTKs) and protein tyrosine phosphatases
(PTPs) is linked to numerous human diseases, including cancer, dia-
betes, obesity, infection, autoimmune, and neuropsychiatric disor-
ders.2,3 Hence, PTKs and PTPs are emerging as high value targets
for therapeutic intervention.3–7 Many drug discovery programs
conducted to date have focused on the PTKs and more than a dozen
small molecule inhibitors targeting the kinases have reached the
market.8 However, the therapeutic benefits of modulating PTPs
are still underexplored despite the fact that several PTPs have been
identified as high value targets.9
Protein tyrosine phosphatase 1B (PTP1B) is prototypic member
of PTP family that appears to be involved in the regulation of several
cellular functions.10 Biochemical and genetic experiments have
established that PTP1B is a key negative regulator of insulin recep-
tor and leptin receptor-mediated signaling pathway and plays a
critical role in insulin and leptin signaling.11 Besides its central role
in the insulin cascade, PTP1B is involved in other important
pathways related with human breast and ovarian cancers.12,13 Con-
sequently, small molecule PTP1B inhibitors that not only serve as
powerful tools to define the physiological roles of PTP1B in vivo,
but also as excellent lead compounds for the development of new
therapeutic agents for type 2 diabetes mellitus, obesity, and cancer.
Various PTP1B inhibitors have been developed over the past dec-
ade.14–16 However, only two candidates have entered clinical trials
while no commercial drugs have been approved till date due mainly
to limited bioavailability.17–19 There are two significant challenges
to develop orally bioavailable, small molecular PTP1B inhibitors14
:
(1) PTP1B shares the close homology with other PTPs, for example,
T-cell protein tyrosine phosphatase (TCPTP) shares a structurally
very similar active site with PTP1B and about 80% homologous in
the catalytic domain, making it difficult to design inhibitors that
are specific for PTP1B,20 and (2) many small molecules that bind
with high affinity in active site are hydrophilic, and as a result they
have poor cell permeability. Therefore, imminent development of
potent and bioavailable PTP1B specific inhibitor remains necessary.
In order to search for new compounds with better PTP1B/TCPTP
inhibitory selectivity and potential bioavailability, benzidine
derivative 1, which has similar scaffold to hepatitis C virus NS5A
inhibitors,21 was identified as novel PTP1B inhibitor (IC50 = 19.27
⇑
Corresponding authors. Tel./fax: +86 510 85329042 (W.-L.W. and B.F.); tel./fax:
+86 21 50800721 (J.L.).
1.80
lM) through high throughput screening of our compound
E-mail addresses: wwenlong2011@163.com (W.-L. Wang), jli@mail.shcnc.ac.cn
(J. Li), fengbainian@jiangnan.edu.cn (B. Feng).
These authors contributed equally to this work.
collection (Fig. 1). This result provided us a chance to explore novel
http://dx.doi.org/10.1016/j.bmcl.2014.03.015
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

1890
W.-L. Wang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1889–1894
small molecule inhibitors of PTP1B. In this study, we designed and
O
O
O
O
synthesized a series of compounds based on the benzidine scaffold,
evaluated their inhibitory activities toward PTP1B, and elucidated
the structure activity relationships (SARs). Selected compounds
were also subjected to selectivity analyses to determine whether
their biological properties made them suitable for further
development.
HN
NH
1
(IC50 =19.27 1.80 µM)
Based on the structure of compound 1, 26 new bis-aromatic
amide derivatives (compounds 2–17, 20–21, 22, 23, 25 and
Figure 1. Chemical structure of hit compound 1.
Table 1
PTP1B inhibitory activities of compounds 2–17, 20–21, 22, 23, 25 and 27–31
R2
Z
Y
R1
X
2 17 20 21 22 23 25 27 31
-
,
-
,
,
,
,
-
a
Compd
X
Y
Z
R1
R2
Inhibition (%) at 20
38.13
lg/mL
IC50
NTb
(lM)
O
O
S
S
2
CH
NH
NH
O
O
3
4
CH
CH
NH
NH
NH
NH
95.20
11.90
11.99 1.25
O
O
O
O
NTb
MeO
MeO
MeO
MeO
MeO
MeO
5
CH
NH
NH
47.37
NTb
OMe
O
OMe
O
6
7
CH
CH
NH
NH
NH
NH
98.59
84.61
18.97 3.85
12.52 1.29
F
F
O
O
O
O
8
9
CH
CH
NH
NH
NH
NH
90.70
43.55
16.54 1.79
NTb
O
O
Boc
N
Boc
N
O
O
H
N
H
N
10
CH
NH
NH
0.70
NTb
O
O
11
12
CH
CH
NH
NH
NH
NH
71.14
10.29
9.50 1.50
NTb
BocN
HN
BocN
HN
O
O
O
O
O
O
O
O
N
N
13
14
CH
CH
NH
NH
NH
NH
95.30
94.09
5.04 1.14
2.65 0.08
F
F
O
O
N
N

W.-L. Wang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1889–1894
1891
Table 1 (continued)
a
Compd
X
Y
Z
R1
R2
Inhibition (%) at 20
93.97
lg/mL
IC50 (lM)
O
O
O
O
N
N
15
16
CH
NH
NH
2.34 0.08
O
O
O
O
O
O
N
N
CH
NH
NH
60.96
14.63 3.50
O
O
O
O
N
N
17
20
CH
CH
NH
CO
NH
CO
69.98
62.75
12.16 0.59
18.54 3.49
H
H
N
N
H
N
H
N
21
22
CH
CH
CO
CO
CO
7.92
NTb
NTb
F
OMe
F
H
NH
31.51
O
O
23
CH
CO
NH
OMe
69.41
10.24 0.82
H
N
25
27
28
CH
N
CO
NH
NH
NH
NH
NH
81.17
86.39
83.89
4.61 0.69
11.05 1.70
5.37 0.56
O
O
O
O
O
O
N
O
O
29
N
N
NH
NH
NH
NH
71.00
82.14
5.96 0.63
7.14 1.19
F
F
O
O
O
O
30
31
N
NH
—
NH
—
58.15
—
26.54 3.65
1.90 0.11
OAc
—
—
—
a
The pNPP assay. IC50 values were determined by regression analyses and expressed as means SD of three replications.
NT means not tested.
OA means oleanolic acid as positive control.
b
c
27–31) (Table 1) were designed and synthesized. Coupling of com-
mercially available benzidine with acyl chlorides yielded com-
pounds 2–8 (Scheme 1). Amide compound 9 was obtained in 80%
Compound 26 was obtained by the literature procedures,22 fol-
lowed by treatment with various acyl chlorides to afford the target
compounds 27–31.
yield by coupling with Boc-
L
-proline. The N-Boc-protecting group
All the synthesized compounds were evaluated for their inhib-
itory activities against PTP1B by the method of p-nitrophenyl phos-
phate (pNPP) using Na3VO4 as positive control,23,24 and the results
are detailed in Table 1. We initially prepared 2–12 by the route
outlined in Schemes 1 and 2, in which we replaced the furan-2-car-
bonyl group on benzidine derivative 1 with various acyl groups.
Among compounds 2–6 with aryl carbonyl substitutes on the ben-
zidine, compound 2 with thiophene-2-carbonyl group showed
poorer enzyme inhibitory activity than compound 1 with furan-
2-carbonyl group. Compound 3 with benzoyl group displayed the
best inhibitory inhibition against PTP1B with IC50 of
of 9 was removed using trifluoroacetic acid (TFA) to yield the
resulting amine 10 (Scheme 2). Amine 12 was obtained using sim-
ilar conditions to compound 10 and treated with acyl chloride to
afford compounds 13–17 (Scheme 2). Compound 19 was formed
by treatment of acid 18 with thionyl chloride using DMF as cata-
lyst, followed by coupling with aromatic amine to yield com-
pounds 20–21 (Scheme 3). Compound 25 was synthesized as
shown in Scheme 4. Compound 22 was obtained via Suzuki cou-
pling reaction and then successively coupled with benzoyl chloride
to give compound 23. After saponification with lithium hydroxide
in aqueous MeOH, compound 24 was obtained in 80% yield, fol-
lowed by coupling with aniline to provide compound 25 in 50%
yield. Synthesis of compounds 27–31 was outlined in Scheme 5.
11.99 1.25
compound 1. Compound 6 with 4-fluorobenzoyl group displayed
similar activity to compound 1, while compound with
lM, exhibited slightly better inhibitory activity than
4

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W.-L. Wang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1889–1894
2 R = thiophen-2-yl
3 R = phenyl
O
O
4 R = 4-methoxyphenyl
5 R = 3,4,5-trimethoxyphenyl
6 R = 4-fluorophenyl
7 R = cyclohexyl
R
R
a
H2N
NH2
HN
NH
8 R = isobutyl
Scheme 1. Synthesis of compounds 2–8. Reagents and conditions: (a) pyridine, RCOCl, DCM, 49–74%.
O
O
O
O
b
a
N
H
N
Boc
N
H
N
Boc
NH
H2N
NH2
NH
HN
HN
10
9
c
O
O
O
O
NBoc
NH
BocN
HN
d
NH
NH
HN
HN
11
12
e
13 R = 4-fluorophenyl
O
O
R
R
O
O
14
15
R = phenyl
N
N
R= furan-2-yl
NH
HN
16 R = cyclohexyl
17
R = isobutyl
13 17
-
Scheme 2. Synthesis of compound 9–17. Reagents and conditions: (a) Boc-
L-proline, EDC, DMAP, DCM, 12 h, 80%; (b) TFA, DCM, reflux, 4 h, 85%; (c) HATU, Et3N, 1-(tert-
butoxycarbonyl)piperidine-4-carboxylic acid, DCM, reflux, 24 h, 82%; (d) TFA, DCM, reflux, 12 h, 90%; (e) RCOCl, Et3N, DCM, 43–60%.
R
NH
O
O
a
b
HOOC
COOH
ClOC
COCl
HN
R
18
19
20-21
20 R = phenyl
21
R = 4-fluorophenyl
Scheme 3. Synthesis of compound 20–21. Reagents and conditions: (a) SOCl2, DMF, 85 °C, 8 h, 92%; (b) amine, Et3N, THF, 4 h, 40–48%.
4-methoxybenzoyl group and 5 with 3,4,5-trimethoxybenzoyl
group displayed poor enzyme inhibitory activity at the concentra-
tion of 20 lg/mL, indicating that electron-donating group on the
aryl carbonyl substitute may not favor the PTP1B inhibitory activ-
ity. Among compounds 7–12, compound 7 with cyclohexanecar-
bonyl group and compound 8 with 3-methylbutanoyl group
slightly improved the enzyme inhibitory activity compared to
compound 1. Compound 9 with (S)-1-(tert-butoxycarbonyl)pyrrol-
idine-2-carbonyl group exhibited poor enzyme inhibitory activity.
Interestingly, compound 11 with 1-(tert-butoxycarbonyl)piperi-
substitutes were changed from –NH– to –CO–. Two biphenyl
dicarboxamide derivatives were synthesized. The enzyme inhibi-
tory activities of compound 20 with phenylamino group and com-
pound 21 with (4-fluorophenyl)amino group dropped obviously
compared to their corresponding compound 3 and compound 6
respectively. This result indicated that the type of amide linkage
between biphenyl group and substitutes may impact the enzyme
inhibition. Then compound 25 with different amide linkages at Y
(–CO–) and Z (–NH–) was designed and synthesized. Interestingly,
compound 25 exhibited great potency (IC50 = 4.61 0.69
the corresponding compound 3 (IC50 = 11.99 1.25 M). Among
the intermediates of compound 25, amine 22 showed poor enzyme
inhibitory activity at 20 g/mL, however, the corresponding com-
pound 23 with benzoyl group exhibited activity with IC50 value
of 10.24 0.82 M. The result revealed that the substitutes on
lM) than
dine-4-carbonyl group with IC50 of 9.50 1.50
l
M increased 2-fold
l
potency compared to compound 1. After removal of Boc group on
compound 11, the enzyme inhibitory activity of compound 12
dropped significantly. This result indicated that free amine on
compound 12 impaired the enzyme inhibitory activity and intro-
duction of various substitutes could have a beneficial effect on
the inhibitory activity. Inspired by this result, various acyl groups
were introduced into amine 12. Compound 14 with benzoyl group
l
l
biphenyl amine might favor the enzyme inhibition.
By replacing a phenyl ring on compound 1 with a pyridinyl ring,
6-(4-aminophenyl)pyridin-3-amine derivatives were synthesized
(Scheme 5). Except compound 31 with 3-methylbutanoyl group,
all of the 6-(4-aminophenyl)pyridin-3-amine derivatives improved
enzyme inhibitory activities compared to their corresponding com-
pounds. Compound 27 with furan-2-carbonyl group showed better
inhibitory activity than compound 1. Compound 28 with benzoyl
group and compound 30 with cyclohexanecarbonyl group showed
2-fold more potent than compound 3 and compound 7 respec-
tively. Compound 29 displayed 3-fold more potent than compound
6. These results demonstrated that the replacement of a phenyl
(IC50 = 2.65 0.08
lM) and compound 15 with furan-2-carbonyl
group (IC50 = 2.34 0.08
l
M) dramatically improved the enzyme
inhibitory activity, 7-fold more potent than hit compound 1.
Compound 13 with 4-fluorobenzoyl group showed about 4-fold
more potent than compound 1. Compound 16 with cyclohexane-
carbonyl group and compound 17 with 3-methylbutanoyl group
showed similar activity to compound 11, which exhibited about
2-fold more potent than compound 1. To further investigate the
SAR, the amide linkages (Y and Z) between biphenyl group and

W.-L. Wang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1889–1894
1893
O
a
b
NH2
MeOOC
NH
B(OH)2
MeOOC
MeOOC
HOOC
22
23
24
c
O
O
NH
O
d
NH
NH
25
Scheme 4. Synthesis of compound 22, 23, 25. Reagents and conditions: (a) 4-bromoaniline, Pd(PPh3)4, Na2CO3, DME/EtOH, 20 h, 22%; (b) Et3N, benzoyl chloride, DCM, 2 h,
65%; (c) LiOH, H2O/MeOH, 80%; (d) aniline, EDC, HOBt, DMAP, DIPEA, DMF, 50%.
For evaluating the inhibitory modality of compound series,
compound 15 was selected for enzymatic kinetic study on PTP1B.24
As shown in Figure 2A, 15 demonstrated a fast-binding inhibition
of PTP1B. The fast-binding inhibition of 15 toward PTP1B may also
exclude that 15 is a nonspecific inhibitor, because nonspecific
inhibitors always show time-dependent behavior and steep inhibi-
tion curve.26 We further determined the inhibition modality of 15
which inhibited PTP1B with the characteristics typical of a compet-
itive inhibitor, as indicated by increased km values and unchanged
Vmax values when the inhibitor concentration was increased
(Fig. 2C). Meanwhile, the result of the Lineweaver–Burk plot con-
firmed 15 as a competitive inhibitor of PTP1B for intersecting at
y-axis of a nest of lines with increased inhibitor concentration
(Fig. 2B). The results indicated that 15 binds the catalytic pocket
of PTP1B and behaves as a competitor to the substrate.
R
O
NH
27
NH2
a
R = furan-2-yl
28 R = phenyl
N
27 31
N
29 R = 4-fluorophenyl
H2N
HN
26
30
R = cyclohexyl
-
31 R = isobutyl
O
R
Scheme 5. Synthesis of compound 27–31. Reagents and conditions: (a) RCOCl,
Et3N, THF, 50–71%.
ring on benzidine core with a pyridinyl ring obviously impacted on
the enzyme inhibition.
In addition to potency improvements, we investigated the
selectivity of compounds with IC50 below 10
l
M, namely, 11, 13–
Given the observed inhibitory activity of compound 15, which
emerged as the most potent inhibitor of PTP1B among all the ana-
logs tested, we proceeded to evaluate its ability to inhibit inside
cells. As showed in Figure 2D, CHO cells overexpressing human
insulin receptor (CHO/hIR) were treated in presence or absence
of compound, then tyrosine phosphorylation level of insulin recep-
tor (p-IR) was detected after stimulated by insulin. Compared with
15, 25 and 28–30 against other PTPs (TCPTP, SHP-1, SHP-2, LAR).
As shown in Table 2, homogeneous T-cell protein tyrosine phos-
phatase (TCPTP) inhibitory activities were investigated simulta-
neously by the same method.23–25 Compound 13, 25 and 29 did
not show obviously enzyme inhibitory activities against TCPTP at
the dose of 20 lg/mL. Compounds 15 and 28 exhibited 5.29-fold
and 4.87-fold greater selectivity for PTP1B than for TCPTP respec-
tively, and showed about twofold increased selectivity than com-
pound 1. Compound 11, 14 and 30 showed similar selectivity to
compound 1. Besides TCPTP, we tested the inhibitory activity of
these compounds on other three homogenous enzymes SHP-1,
SHP-2, and LAR.24 As shown in Table 2, we noticed that all of com-
pounds had no visible activities against LAR and compound 15 did
not show obviously enzyme inhibitory activities against SHP-1 and
negative control of DMSO, compound 15 ranging from 5
lM to
20 M greatly improved p-IR level. This result indicates that com-
l
pound 15 shows well membrane permeability and could protect
insulin pathway signaling on the cellular level.
In conclusion, a series of bis-aromatic amide derivatives were
synthesized and identified as PTP1B inhibitors with IC50 in the
micromolar range. Among these, the representative compound
15 had no visible activities against receptor-like transmembrane
LAR, SHP-1 and SHP-2. More importantly, compound 15 exhibited
good selectivity for PTP1B over TCPTP, and cellular activity for
SHP-2 at the dose of 20 lg/mL, while compound 1 displayed inhib-
itory activities against SHP-1 and SHP-2.
Table 2
The IC50 values of compounds 1, 11, 13–15, 25 and 28–30 against PTPs
a
a
Compd
IC50
(lM)
TCPTP/PTP1B
IC50
(lM)
PTP1B
TCPTP
LAR
SHP-1
SHP-2
1
11
13
14
15
25
28
29
30
PCc
19.27 1.80
9.50 1.50
5.04 1.14
2.65 0.08
2.34 0.08
4.61 0.69
5.37 0.56
5.96 0.63
7.14 1.19
1.90 0.11
50.96 4.46
21.19 1.16
NAb
7.62 0.52
12.39 1.46
NAb
2.64
2.23
—
2.88
5.29
—
4.87
—
3.20
—
NAb
38.76 3.39
18.18 1.37
NAb
52.07 6.08
NAb
NAb
NAb
NAb
NAb
NAb
NAb
NAb
NAb
NAb
NAb
NAb
NAb
26.16 3.44
NAb
NAb
NAb
NAb
NAb
17.76 2.35
19.74 3.05
22.86 2.35
4.23 0.55
NAb
NAb
NAb
16.54 1.35
16.49 1.76
34.66 7.54
SHP-1, SH2-containing protein tyrosine phosphatase-1; SHP-2, SH2-containing protein tyrosine phosphatase-2; LAR, leukocyte antigen-related tyrosine phosphatase.
a
The pNPP substrate and 3-o-methylfluorescein phosphate (OMFP) substrate were utilized in PTP1B/TCPTP assay, and SHP-1/SHP-2/LAR assay, respectively; IC50 values
were determined by regression analyses and expressed as means SD of three replications.
b
NA: no activity (compound inhibitory ratio lower than 50% at the dose of 20
PC: positive control; oleanolic acid was for PTP1B and TCPTP, Na3VO4 was for SHP-1, SHP-2 and LAR.
l
g/mL).
c

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W.-L. Wang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1889–1894
Figure 2. Characterization of 15 to PTP1B. (A) Fast-binding inhibition of PTP1B by 15; (B) typical competitive inhibition of 15 shown by Lineweaver–Burk plot; (C) the initial
velocity determined with various concentrations of pNPP at various fixed concentrations of 15; and (D) effect of 15 on tyrosine phosphorylation of insulin receptor b in CHO/
hIR cells. PC (positive control): sodium orthovanadate (250 lM); D (negative control): DMSO.
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Acknowledgments
This work was supported by National Natural Science Founda-
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preparation procedures is available online. Biological assays were
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