Identification of novel urea derivatives as PTP1B inhibitors: Synthesis, biological evaluation and structure-activity relationships

Article abstract of DOI:10.1039/c3md00138e

The protein tyrosine phosphatase 1B (PTP1B) is an attractive target for the treatment of type 2 diabetes. A series of substituted 1,3-benzyl urea has been synthesized and evaluated for PTP1B inhibitory, antidiabetic and antidyslipidemic activities. The most active compound of the series 5b showed 79.4% PTP1B inhibition and 20.7% blood glucose lowering in the STZ model. It also lowered the serum cholesterol level by 16.3% and significantly increased the serum HDL-cholesterol by 46.8%. The high activity of compound 5b has been explained by docking studies.

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CONCISE ARTICLE
Identification of novel urea derivatives as PTP1B inhibitors: Synthesis,
biological evaluation and structure–activity relationships
Swati Gupta,‡a Kanika Varshney, ‡a Rohit Srivastava,b Neha Rahuja,b Arun K Rawat,b Arvind K
Srivastava,b and Anil K Saxena*a
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
The protein tyrosine phosphatase 1B (PTP1B) is an attractive target for the treatment of type 2 diabetes. A series of substituted 1, 3-
benzyl urea has been synthesized and evaluated for PTP1B inhibitory, antidiabetic and antidyslipidemic activities. The most active
compound of the series 5b showed 79.4% PTP1B inhibition and 20.7% blood glucose lowering in STZ model. It also lowered the serum
10 cholesterol level by 16.3 % and significantly increased the serum HDL-cholesterol by 46.8%. The high activity of the compound 5b.has
been explained by docking studies.
We have previously reported the synthesis and antidiabetic
Introduction
activity
of
N-[2-(4-methoxy-phenyl)ethyl]
acetamide
50 derivatives(1).10 Encouraged by the results of our previous work,
and in order to further optimize the PTP1B inhibitory activity,
herein we report novel urea derivatives as potent PTP1B
inhibitors.
The Type 2 diabetes is severe and growing disease in epidemic
proportions world-wide. According to International Diabetes
15 Federation (IDF), diabetes is the one of the major challenging
health problems of 21st century.1 India, China, and United States
are expected to have the largest number of diabetic people by
2030, and India has been considered to be the diabetes time
bomb.2 Diabetes is caused due to the hepatic insulin resistance
20 along with pancreatic cell defects which leads to the risk of
premature death because of cardiovascular complications,
nephropathy and retinopathy.3
The structure-activity relationship (SAR) studies have
55 been carried out by systemic molecular modulation on the hit
molecule 1 (IC50=69µM). The molecule 1 was divided into three
regions, the substituted aromatic ring (region I); around acyl
group (region II); and the naphthalene ring (Region III) (Fig.1).
Initially considering the importance of NH group in increasing
60 the PTP1B inhibitory activity probably due to hydrogen bonding
with Gln 262, 10 the acetamide group was replaced by urea moiety
to probe the possibility of additional hydrogen bonding with the
side chains of Gln262. Further studies were centered on systemic
substitution by different R1 and R2 groups around region I and III.
65 It was observed by the docking pose of the compound 1 that the
oxygen of 4-methoxyphenyl group forms only one hydrogen
bonding interaction with the active site residue (Arg221). So it
appeared of interest to insert nitro group which may show
additional interactions and thus may enhance the PTP1B
The protein tyrosine phosphatase 1B (PTP1B) is the
negative regulator of insulin and leptin receptor pathway and is
25 considered as an attractive target for the treatment of diabetes and
5, 6
obesity.
The PTP1B inhibition leads to the enhanced insulin
action by prolonging the phosphorylation state of insulin
receptors.4 In a recent landmark study, PTP1B deficient mice
showed increased insulin sensitivity and resistance to diet-
30 induced obesity.7,8
Despite of the continuous efforts, no PTP1B inhibitor
has successfully completed the clinical trials. It may be due to the 70 inhibitory activity. Therefore, in region I, the methoxy group was
low cell permeability and bioavailability of these inhibitors.9
Efforts are made to discover orally active and selective PTP1B
35 inhibitors which may also be useful for probing signal
transduction pathways as well as for the treatment of diabetes and
obesity.
replaced by the hydrogen and nitro group to see the effect of
hydrogen bonding on activity. In the third region different
substituted aryl groups were introduced in place of naphthalene
group because this group showed no interaction in the catalytic
75 and non-catalytic sites thus making this transformation suitable to
modulate the pharmacokinetic properties.
In recent years we have been engaged in the design, synthesis and
evaluation of novel PTP1B inhibitors of diverse classes.10-12
Chemistry
40 aMedicinal and Process Chemistry Division, CSIR-Central Drug Research
Institute, Lucknow, India.; Division of Biochemistry, CSIR-Central
The strategy adopted for the synthesis of the title compounds has
been outlined in scheme 1, where the key intermediates, namely,
b
Drug Research Institute, Lucknow, India. *Tel: +91-5222624273, 80 substituted 1-benzylureas (3) were synthesized using substituted
Fax:+91-52226123405, Email: anilsak@gmail.com
Electronic Supplementary Information (ESI) available: Experimental
45 procedures, characterization data, protocols of biological assays. See
DOI: 10.1039/b000000x/
benzylamine (1) and urea (2) according to the known reported
methods.13 The substituted 1-benzylureas derivatives (3a-f) were
reacted with the substituted benzaldehydes in the presence of
titanium isopropoxide and the resulting imine intermediates were
85 reduced by sodium borohydride to give the corresponding
substituted 1-benzyl-3-hetroarylureas (4a-4k,5a-5i).
‡These authors contributed equally.
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CONCISE ARTICLE
Scheme 1.
Fig.1
Fig.1 Structure of the previously reported acetamide analogue (1) as PTP1B inhibitor; Scheme 1: Reagents and Conditions (i) Water, HCl, 100oC, 6-7 h
(ii) Aromatic aldehydes, Ti(OPr)4, NaBH4, 24 h
Table:1 In vitro PTP1B inhibitory and in vivo antihyperglycemic activity in STZ model for compound (4a-4k, 5a-5i)
% lowering on blood
Compd.
R1
R2
%
inhibition
(
glucose
level
IC50 value in µM) (100mg/kg)
0-5hr
-
0-24 hr
4a
4b
4c
4d
4e
4f
H
H
H
H
H
H
2-NO2Ph
3-NO2Ph
2.10
2.40
0.90
13.7
14.9
18.9
-
-
-
-
-
-
-
-
-
-
-
4-NO2Ph
2,6-diCl-3,4-diOCH3Ph
3-methoxy-4-hydroxyPh
3,5-di-tert-butyl-2-
hydroxyPh
4g
H
2,4,6-trimethoxyPh
2-thiophene
78.8 (7.6)
31.2
16.1**
18.6**
4h
H
-
-
-
-
4i
H
5-(4-nitrophenyl)furan
5-chloro-1H-indol-3-yl
4-acetamidoPh
3-ChloroPh
21.4
-
-
4j
H
19
4k
H
60.93 (9.39)
32.9
14.2* 14.8*
5a
3-Nitro
3-Nitro
3-Nitro
3-Nitro
3-Nitro
3-Nitro
3-Nitro
3-Nitro
3-Nitro
-
-
5b
2-NO2Ph
79.4 (7.47)
56.6 (9.91)
2.85
20.4*** 21.7***
5c
2,6-diCl-3,4-diOCH3Ph
4-MethoxyPh
7.26
2.54
5d
-
-
-
-
-
-
5e
3,5-dimethoxyPh
3,4,5-trimethoxyPh
6-(3-nitrophenyl)pyridine
2-furan
2.81
-
-
-
-
5f
5g
7.50
40
5h
46.8
5i
5-(4-nitrophenyl)furan
-
68.4 (8.06)
60
18.4*** 20.0***
Suramin
Metformin
-
-
-
-
21*** 23.3***
-
-
Values are mean ± SEM, n=6, p< 0.05 * p<0.01** and p<0.001***
5
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Therefore, a set of 21 substituted urea derivatives with different
functionalities at R1and R2 were synthesized and evaluated
with varying concentration of substrate IR5 (sequence from the
insulin receptor ß subunit domain provided in the kit) from 10 to
against protein tyrosine phosphatase 1B (PTP1B). The effect of 60 100µM. The Lineweaver-Burk double reciprocal plot in Fig. 2
the synthesized compounds on PTP1B was studied using
colorimetric, non-radioactive PTP1B drug discovery kit-BML-
AK 822 from Enzo Life Sciences, USA. The assay was done
according to the Kit protocol and first all the compounds were
shows intercept of all lines (obtained with 0µM, 5 µM, 10µM and
20µM compound 5b concentration) converging at y-axis (1/Vmax
), whereas slope and x-axis intercept (-1/Km ) vary with inhibitor
concentration which is a characteristic of competitive inhibition,
5
evaluated for PTP1B inhibition at 10 µM concentration. Further 65 therefore the evaluated compound 5b is a competitive inhibitor of
compounds showing more than 50% inhibition against PTP1B
10 were evaluated at five different concentrations to calculate their
IC50 value. Suramin was used as a reference standard.
PTP1B. The Km value for the IR5 substrate was determined
from the lineweaver burk plot shown in the Fig.2 and was found
81.4 μM. The Ki value was determined by plotting the slope
values vs [I]. The resulting secondary plot or "replot" have a Y-
70 axis intercept of Km/Vmax and a slope of Km/VmaxKi. The value of
Ki was calculated from intercept on X-axis of this replot and
found 7.88µM which is less than the IC50 of the substrate IR5
(85µM) indicating that the inhibitor binds the enzyme better than
the substrate.
The antidiabetic activity including PTP1B inhibitory
activities of the urea derivatives are presented in Table 1. It was
observed from the results that the substitution at R1 and R2
15 positions influenced the biological activity of the synthesized
analogues (4a-4k, 5a-5i). These compounds in general showed
enhanced PTP1B inhibitory activity in comparison to the
compounds with acetamide groups reported earlier.10 Initially the
variation at R1 position (region I, R1= H , 3-nitro) were performed
20 to derive structure activity relationship. Keeping R1 as H, a
systemic evaluation of R2 (region III) with different groups that
varied in size and polarity were explored (4a-4k). This series of
compounds with simple phenyl ring in region I was less active
than the series with 3-nitro group at R1 position in region I. The
25 compounds 4h, 4i and 4j with heterocyclic rings at R2 position
and R1 as H showed less activity with 31.2%, 21.4% and 19%
PTP1B inhibition respectively. The compounds 4a and 4d having
2-nitro and 2,6-dichloro-3,4-dimethoxyphenyl at R2 position
showed highly reduced activity with 2.10% and 13.7% PTP1B
30 inhibition. The compounds 4b, 4c, 4e and 4f also did not show
PTP1B inhibitory activity. However, the compounds 4g and 4k
having 2,4,6-trimethoxy phenyl group, and 4- acetamidophenyl
at R2 position showed good activity with 79.8% and 60.93%
PTP1B inhibition respectively. Interestingly, majority of
35 analogues with 3-nitro substituent at R1( region I) showed higher 75 Fig. 2 Competitive inhibitory profile of compound 5b
inhibitory activity as compared to the corresponding analogue(s)
with hydrogen. The compound 5b with 3-nitro substituent at R1
and 2-nitrophenyl at R2 ( region III) was the most active
Molecular modelling
compound of the series with 79.4% inhibition (IC50= 7.47 µM).
40 The compounds 5g, 5h, 5i, with heterocyclic rings substituted at
R2 position and 3-nitro group at R1 position exhibited moderate
In continuation of our earlier work where the docking studies was
successfully applied to elucidate essential structural requirements
15
for molecules acting on the same receptor/enzyme10-12,
we
activities (31- 68% inhibition; 5i, IC50= 8.06 µM) but better than 80 herein report the docking studies of the most active compound 5b
the compounds with R1 as H, while the presence of electron
releasing group at R2 position in compounds 5d, 5e, 5f proved
45 detrimental to the PTP1B inhibitory activity (2- 8% inhibition).
However, the compound 5a with 3-chlorophenyl group and the
compound 5c with 2,6-dichloro-3,4-dimethoxy phenyl group at
R2 position showed 33% and 56.9% PTP1B inhibition
respectively.
with the PTP1B enzyme active site to gain an insight and
understanding of the important interactions with the crucial
amino acid residues using the GOLD docking software.16
The binding pose analysis of the most active compound 5b
85 clearly provided rational explanation to its higher potency as
compared to the corresponding acetamide derivatives as
envisaged by us where the additional hydrogen bonding of both
the NH groups in the urea moiety in compound 5b with the
amidic oxygen of Gln262 was observed. The nitro group at 3-
90 position of phenyl ring in region I was also involved in hydrogen
bonding interaction with the active site residues Arg221, Asp181
and Ser216 providing the anchorage of this molecule into the
active site of PTP1B. These catalytic residues, Arg221 and
Asp181, also play a key role in the binding mode of the co-
95 crystallized ligand.17 (PDB ID-2F70; Fig.3) It is known that the
site B of PTP1B differs from that of TCPTP by a few amino acids
50 Kinetics Measurements and Mechanism of
Inhibition
Kinetics measurements and mechanism of inhibition was studied
using the PTP1B tyrosine phosphatase drug discovery kit BML
AK 822 from Enzo life science USA as used for the study of the
55 percentage inhibition. For determination of type of inhibition we
have performed the activity assay at different concentration of
0µM, 5 µM, 10µM and 20µM of the most active compound 5b
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Medicinal Chemistry Communications
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and thus offers an opportunity to improve selectivity over
interaction with the site B is essential for achieving selectivity
19
TCPTP.18,
The 2-nitrophenyl ring in the region III of the
over TCPTP. Hence, the favorable interactions of compound 5b
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compound 5b showed potential to make hydrogen bond
interactions with the secondary binding site (site B) of PTP1B,
characterized by Arg24 and Arg 254. As mentioned earlier
with the sites A and site B of PTP1B enzyme suggest that this
DOI: 10.1039/C3MD00138E
compound may be selective over TCPTP.
5
10
Fig. 3. A) Pose attained by compound 5b (pink) and co-crystallized ligand of PDB Id: 2f70 (green) in the active site of PTP1B
; B) Predicted conformation of compound 5b in the binding site cavity of PTP1B; C) Analysis of predicted binding pose of 5b with PTP1B
The 3-nitrophenyl ring of the compound 5b also showed pi-pi
interaction with Tyr46 and Phe 182 similar to the co-crystallized
15 ligand. However, the higher activity of the compound 5b than the
co-crystallized ligand (PDB ID: 2F70, IC50= 33.5 µM) may be
due to the additional hydrogen bonding interaction by the urea
group of 5b with Gln 262.
In vivo biological activity
20 Based on the high PTP1B inhibitory activity in vitro a limited
number of compounds with more than 50% PTP1B inhibition
(Table 1) were evaluated in vivo in Streptozotocin-induced rats
model (STZ). Among these, the compounds 4g, 5b and 5i showed
lowering of blood glucose level by 16.1 %, 20.4 % and 18.4%
25 during 5h and 18.6 %, 21.7 % and 20.0 %, during 24h,
respectively (Fig. 4).
Fig.4 Antihyperglycemic activity of test compounds in low dosed
Streptozotocin-induced diabetic rats. Statistical analysis was made by
Dunnet test (Prism software 3)
Inspired by the findings the most potent compound 5b was further
To observe the effect of drug on glucose tolerance an
evaluated for anti-hyperglycemic and antidyslipidemic activities 40 OGTT was conducted on day 10th and 15th during the course of
in C57BL/KsJ-db/db mice.(Table 2). The compound 5b at the
30 dose of 30 mg/kg showed significant blood glucose lowering
from day 8 till the end of the experiment as compared to the
reference drug pioglitazone which showed significant lowering in
dosing in overnight fasted mice. Compound 5b significantly
improves the glucose tolerance by 24.2 and 35.9 % (p<0.01) at
dose level 30.0 mg/kg body weight on day 10 and 15 respectively
whereas the standard drug pioglitazone showed a significant
blood glucose from day 6 till the end of the experiment at the 45 improvement of 40.8 and 52.9% (p<0.01) at dose level 10.0
dose of 10mg/kg (Fig. 5).
mg/kg body weight on day 10 and 15 respectively as compared to
vehicle treated sham control group (Fig. 6).
35
Table 2:
Antihyperglycemic and antidyslipidemic activity in db/db mice( % efficacy, 10 and 15 days)
Antihyperglycemic Antidyslipidemic Insulin resistant reversal
Compd No.
10 days
15 days
TG
CHOL
HDL
Fasting
blood
glucose
Serum
insulin
level
HOMA-
index
5b
24.1
40.8
35.9
52.9
8.9
16.3
9.17
46.8
11.1
52.3
34.5
69.7
70.3
Poiglitazone
12.6
64.7
46.1
4
|
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Fig 5. Effect of compound 5b and Pioglitazone on blood glucose of db/db mice; Fig 6. Effect of compound 5b and pioglitazone on OGTT on day 10 (A)
and day15 (B) posttreatment
Treatment of compound 5b also restores the altered
serum lipid profile as evident from the Fig. 7. The compound 5b
significantly lowers the serum cholesterol level by 16.3 %
(p<0.05) with significant increase in serum HDL-cholesterol by
46.8% (p<0.05). Treatment with the standard drug pioglitazone
significantly declines the serum triglyceride level by 12.6%
compound 5b than the co-crystallized ligand (PDB Id: 2F70).
Further, the compound 5b also showed promising
antihyperglycemic, antidyslipidemic and insulin resistant reversal
55 activities in vivo in STZ model and db/db mice model. Thus these
studies may be helpful in developing novel PTP1B inhibitors
with improved pharmacological properties.
5
10 (p<0.05). Insulin resistance is one of the characteristic features of
db/db mice. Decreased insulin sensitivity leads to hyperglycemia,
hyperinsulinemea. Treatment with compound 5b, near normalizes
the fasting blood glucose by 52.3% (p<0.01) and restores the
altered insulin level by 34.5% (p<0.01) in treated diabetic mice as
15 compared to vehicle treated control group as shown in Fig 8A
and 8B. Homeostatic model assessment (HOMA) is a method
used to quantify insulin resistance on the basis of fasting blood
glucose and fasting serum insulin level. Treatment with
compound 5b significantly improves the insulin resistance state
20 by improving the HOMA-index by 69.7% (p<0.01) (Fig 8C).
Given the observed potency of 5b, we proceeded to
evaluate the ability of 5b to inhibit the PTP1B inside the cell.
Previous studies have demonstrated that PTP1B serves as a
negative regulator of the insulin activated signaling pathways by
25 catalyzing the dephosphorylation of the insulin receptor β (IRβ)
subunit. It is evident from the western blot analysis that inhibition
of PTP1B with compound 5b at the oral dose of 30 mg/kg dose
significantly improved the insulin signaling and sensitivity which
is observed with the enhanced expression of phosphorylated-
30 IRS1 protein in skeletal muscle of db/db mice. The compound 5b
resulted in enhancing the expression of p-IRS1 by 1.25 fold
whereas reference drug pioglitazone showed an increase of 1.37
fold in expression of p-IRS1 as showed in Fig. 8D. Thus, the
inhibition of PTP1B by compound 5b stimulated the
35 phosphorylation of IRS1 protein which ultimately provides the
docking site for the intermediate receptors in the downstream
insulin signaling.
Fig 7. Effect of compound 5b on serum lipid profile
Fig 8. Effect on (A) Fasting blood glucose,
60 (B) Serum insulin level, (C) HOMA-index,
(D) Western blot analysis of p-IRSI in
skeletal muscle of db/db mice, 40 µg of
protein was resolved on SDS-PAGE and
evaluated for levels of p-IRS1. The
65 experiments were repeated three times and
values are means ± SEM of three
Conclusions
independent experiments. The blot shown
were representatives of the indicated groups and the densitometric
analyses of the same are given below. *p< 0.05, **p < 0.01
In summary, a series of novel benzylurea derivatives was
40 designed, synthesized and evaluated against PTP1B enzyme.
Among the 20 synthesized compounds five compounds showed
good PTP1B inhibitory activity namely 4g (7.6 μM), 4k (9.39
μM), 5b (7.47 μM), 5c (9.91 μM) and 5i (8.06 μM). The docking
study performed on the most active compound 5b provided
45 rational explanation to its higher potency as compared to the
corresponding acetamide derivatives as envisaged by us. The
compound 5b interacts well with the active site residues Arg221,
Asp181 and Gln262. It also showed good interaction with
secondary binding site residues Arg24 and Arg 254 which may
50 attribute to its selectivity over highly homologous phosphtase
TCPTP. The docking studies also explained higher activity of
70
Acknowledgement
We thank Sophisticated Analytical Instruments Facility, CDRI
for providing analytical data. The authors are also thankful for
financial assistance by Indian Council of Medical Research
75 (ICMR) (S.G), Council of Scientific and Industrial Research
(CSIR) (K.V, R.S, N.R, A.K.R) and to Mr. Zahid Ali and Mr. A.
S. Kushwaha for technical assistance. The CDRI communication
number allotted to this manuscript is AKS-613.
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DOI: 10.1039/C3MD00138E
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