Discovery of potent, selective and orally bioavailable triaryl-sulfonamide based PTP1B inhibitors

Article abstract of DOI:10.1016/j.bmcl.2011.11.122

A novel series of pTyr mimetics containing triaryl-sulfonamide derivatives (5a-r) are reported as potent and selective PTP1B inhibitors. Some of the test compounds (5o and 5p) showed excellent selectivity towards PTP1B over various PTPs, including TCPTP (

Full text of DOI:10.1016/j.bmcl.2011.11.122

Bioorganic & Medicinal Chemistry Letters 22 (2012) 1111–1117
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of potent, selective and orally bioavailable triaryl-sulfonamide based
PTP1B inhibitors q
Dipam Patel a,b, , Mukul Jain a, Shailesh R. Shah b, , Rajesh Bahekar a, , Pradip Jadav a, Amit Joharapurkar a,
⇑
⇑
⇑
Nirav Dhanesha a, Mubeen Shaikh a, Kalapatapu V.V.M. Sairam a, Prashant Kapadnis c
a Zydus Research Centre, Sarkhej-Bavla, N.H. 8A Moraiya, Ahmedabad 382210, India
b Department of Chemistry, Faculty of Science, M.S. University of Baroda, Vadodara 390002, India
c Medical Research Council, Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of pTyr mimetics containing triaryl-sulfonamide derivatives (5a–r) are reported as potent
and selective PTP1B inhibitors. Some of the test compounds (5o and 5p) showed excellent selectivity
towards PTP1B over various PTPs, including TCPTP (in vitro). The lead compound 5o showed potent anti-
diabetic activity (in vivo), along with improved pharmacokinetic profile. These preliminary results con-
firm discovery of highly potent and selective PTP1B inhibitors for the treatment of T2DM.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 8 September 2011
Revised 11 November 2011
Accepted 28 November 2011
Available online 6 December 2011
Keywords:
Triaryl sulfonamide
pTyr mimetics
PTP1B inhibitor
TCPTP
Type 2 diabetes mellitus (T2DM)
Metabolic disorders
Over the past decade, there has been an alarming increase in the
metabolic syndrome such as obesity and diabetes.1,2 Patients suffer
from obesity-induced type 2 diabetes (diabesity) are at increased
risk of cardiovascular diseases and pose huge economic burden
bind to the active site (Site-1/A).12 However, achieving PTP1B
selectivity over closely associated PTPs (PTP , LAR, CD45, VHR,
a
SHP-1, SHP-2 and T-cell protein tyrosine phosphatase (TCPTP)) is
one of the major challenge, as the closely associated PTPs share a
high degree of sequence homology (92%).13 Lack of oral bioavail-
ability is another aspect in the development of potent and selective
PTP1B inhibitors, as the majority of the active site directed PTP1B
inhibitors exhibit limited cell permeability.14,15
on healthcare services.3 Clinically type
2 diabetes mellitus
(T2DM) is characterized by persistent hyperglycemia, either due
to defects in insulin secretion, insulin resistance or both.4 Currently
diabetic patients are treated with various oral antihyperglycemic
agents; however, over a period of time, T2DM subjects lose their
response to these agents and thereby require insulin therapy.
Except incretin therapies, most of the available antihyperglycemic
agents, including insulin promote weight gain, which further
aggravates obesity associated cardiovascular risk and insulin resis-
tance.5–9 Thus, there is an urgent need to develop novel agents for
glycemic control.
Protein tyrosine phosphatase 1B (PTP1B) enzyme acts as a neg-
ative regulator in insulin signaling pathways. Inhibition of PTP1B
enzyme activity exhibits potential for enhancing insulin action
by prolonging the phosphorylated state of the insulin receptor.10
Several structurally diverse small-molecule based PTP1B inhibitors
have been developed.11 Initially, PTP1B inhibitors were designed to
An additional non-catalytic aryl-phosphate binding site (site-2/
B) was also identified, proximal to the catalytic-phosphate binding
site.13 The site B of PTP1B differs from that of TCPTP by a few amino
acids (F52Y and A27S) and thus offers an opportunity to improve
selectivity over TCPTP.16 Based upon this dual binding site concept,
recently, we reported, effect of bidentate pTyr mimetics (Dif-
luoromethylphosphonates (DFMP)/Difluoromethylsulfonamide (D
FMS)/Isothiazolidinone (IZD)) on benzotriazole-scaffold which lead
to a discovery of an orally active dual binding-site PTP1B inhibitors
(Compound 1; Fig. 1).17 As a part of our ongoing research on PTP1B
inhibitors, herein, we report incorporation of monodentate pTyr
mimetics (DFMP/DFMS/IZD) on triaryl sulfonamide based-scaffold
(Compound 2; Fig. 1).18 Although selectivity, pharmacodynamic
(PD) and pharmacokinetic (PK) profile of compound 2 is not re-
ported, however, in vitro it showed good PTP1B inhibitory activity
(IC50: 74 nM).18 Therefore, the triaryl sulfonamide based scaffolds
were specifically selected to design dual binding PTP1B inhibitors
(5a–r). The in vitro PTP1B inhibitory activity and subtypes-selectiv
q
ZRC communication No: 384 (Part of PhD thesis work of Mr. D. Patel).
⇑
Corresponding authors. Tel.: +91 2717 665555; fax: +91 2717 665355.
E-mail addresses: dipam.patel@rediffmail.com (D. Patel), Shailesh-chem@msu
baroda.ac.in (S.R. Shah), rajeshbahekar@zyduscadila.com (R. Bahekar).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.11.122

1112
D. Patel et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1111–1117
F
F
Br
PO3H2
N
N
PO3H2
N
O
O
F
F
F
N
Compd PTP1B
TCPTP
Selectivity
O
S
F
No
(IC50; µM) (IC50; µM)
PO3H2
Ph
1
0.005
0.074
0.580
NA
116
NA
2
Br
N
N
HO2C
O
S
1
2
Figure 1. Structurally diverse small molecule based-PTP1B inhibitors.
ity of all the test compounds 5a–r were assessed using enzymatic as-
say (in vitro).19 Furthermore, based on the in vitro results, highly po-
tent and selective test compounds 5o and 5p were subjected in vivo,
to determine their antidiabetic effect and PK profile.20,21
plates (5k–n) or its fluoro analogues (5o–r). Depending on the nat-
ure of the substitutents, the tested compounds showed varying
degrees of PTP1B inhibitory activity (Tables 1 and 2).
Within the first series (5a–j), the first set of compounds (5a–f)
containing DFMP-substituted benzyl groups at R1 (5a–d) showed
diverse PTP1B inhibitory activity depending on the DFMP group
position (meta vs para) on the benzyl ring and the ortho substitu-
tents (hydrogen or halogen). Compound 5b, with a m-DFMP group,
showed weak PTP1B inhibitory activity relative to that of p-DFMP
(2), whereas compound 5a, containing p-DFMP and o-bromo
substitution to DFMP, showed good PTP1B inhibitory activity.
Replacement of o-bromo analogues (5a–b) with more electronega-
tive o-fluoro derivatives (5c–d), showed improved PTP1B inhibi-
tory activity. Bioisosteric replacement of the p-DFMP group in
compound 5a with p-DFMS (5e and 5f) showed comparable
in vitro PTP1B inhibitory activity, suggesting that the highly nega-
tively charged DFMP group can be replaced with a DFMS group to
overcome the issue of low permeability. Among the 5e and 5f
tested, 5f showed improved PTP1B inhibitory activity, which could
be due to increase in the electronegativity and decrease in the ste-
ric bulk (5e: ortho-bromo vs 5f: ortho-fluoro) adjacent to the DFMS
group. The second set of compounds containing IZD-substituted
benzyl groups at R1 (5g–j) showed weak PTP1B inhibitory activity,
irrespective of their ortho substitutents. Among the second set
(5g–j), ortho-fluoro derivative (5j) was found to be most potent,
whereas the ortho-methyl (5h) and ortho-bromo (5i) derivatives
were found to be equipotent. Unsubstituted derivative (5g) was
found to be least active, with the set.
Synthesis of the title compounds 5a–r was carried out as
depicted in Scheme 1, following the modified literature proce-
dure.18c Treatment of substituted benzenesulfonyl chloride 3 with
primary amine in the presence of N,N-diisopropylethylamine gave
mono-substituted sulfonamide 4. Alkylation of the compound 4
with appropriate electrophile gave the di-substituted sulfonamides,
which were subsequently converted to 5a–r by treatment with tri-
methylsilyl bromide/trifluoracetic acid to hydrolyze the t-butyl
esters and the phosphonate diethylesters. All the titled compounds
and intermediates were characterized with their physical, analyti-
cal and spectral data (13C NMR, 1H NMR and ESI MS). Elemental
analyses were determined within 0.04% of theoretical values. Over-
all, 5a–r was prepared in good yield, under the mild reaction condi-
tions. The percentage yield in the final step was found to be in the
range of 60–80%. The ESI MS and NMR spectral data of all the syn-
thesized compounds were also found to be in conformity with the
structures assigned and ensure the formation of the compounds
5a–r (see Supplementary data for analytical and spectral data).
The in vitro PTP1B inhibitory activity (p-NPP assay) was deter-
mined in order to establish the structure–activity relationship
(SAR). As shown in Tables 1 and 2, two series of the compounds
were prepared by substituting DFMP/DFMS/IZD-benzyl groups
(5a–j) or with DFMP/DFMS-substituted naphthyl/quinolinyl tem-
plates (5k–r) at position R1. In the first series (5a–j), two sets of
compounds were prepared by substituting DFMP/DFMS benzyl
groups (5a–f) or IZD-substituted benzyl templates (5g–j), while
in the second series (5k–r), two sets of compounds were prepared
by substituting DFMP/DFMS-substituted naphthyl/quinolinyl tem-
The second series of compounds with position R1 as DFMP/
DFMS-substituted naphthyl/quinolinyl templates (5k–r) showed
potent PTP1B inhibitory activity. Within the second series, the first
set of compounds containing DFMP-substituted naphthyl/quinoli-
O
CO2H
O
S
CO2H
R1
O
S
3
CO2H
O
O
O
O
ii, iii
i
S
NH
N
O
O
Cl
S
S
N
N
N
N
4
5(a-r)
Scheme 1. Synthesis of compounds 5a–r. Reagents and conditions: (i) thiadiazolyl-C6H4-CH2-NH2, CH2Cl2, DIEA, 25 °C, 5 h; (ii) R1-X, K2CO3, CH3CN, 70 °C, 4 h; (iii) TMSBr,
CH2Cl2, ꢀ15 °C, 3 h or TFA, CH2Cl2, 2 h.

D. Patel et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1111–1117
1113
Table 1
The In vitro PTP1B inhibitory activity and selectivity of test 5a–j
O
CO2H
R1
O
O
S
N
S
N
N
Compd No.
R1
PTP1Ba IC50 (nM)
TCPTPb IC50 (nM)
F
F
2
78 02
50 03
546 12 (ꢁ7)c
PO(OH)2
Br
F
F
5a
5b
5c
5d
750 13 (ꢁ15)c
PO(OH)2
Br
288 08
F
F
F
(HO)2OP
(HO)2OP
F
F
35 04
870 07 (ꢁ24)c
PO(OH)2
F
F
141 10
F
Br
F
F
5e
5f
47 04
31 02
SONH2
F
F
F
620 08 (ꢁ20)c
SONH2
O
NH
O
5g
5h
5i
500 10
470 11
480 11
S
O
O
O
NH
O
S
S
O
NH
O
O
Br
(continued on next page)

1114
D. Patel et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1111–1117
Table 1 (continued)
Compd No.
R1
PTP1Ba IC50 (nM)
TCPTPb IC50 (nM)
O
NH
O
5j
460 12
S
O
F
a
Enzymatic assay was carried out in 96-well plates. The initial rate of PTPase-catalyzed hydrolysis of pNPP was measured at
405 nm. IC50 value was determined under fixed pNPP concentration of 1 mM (n = 3; represents Mean SD).
b
Selected test compounds which were screened for TCPTP inhibitory activity also showed >5000-fold selectivity over CD45,
LAR, SHP-1 and SHP-2 enzymes (data not shown).
c
Fold selectivity calculated as ratio of average IC50 values of TCPTP/PTP1B inhibitions.
Table 2
The In vitro PTP1B inhibitory activity and selectivity of test 5k–r
Compd No.
R1
PTP1Ba IC50 nM
TCPTPb IC50 nM
Br
Br
Br
Br
F
5k
17 01
PO(OH)2
F
F
F
F
F
F
F
F
F
5l
18 03
39 03
41 05
PO(OH)2
F
N
N
N
N
5m
5n
5o
5p
5q
5r
SONH2
F
SONH2
F
9
01
870 05 (ꢁ96)c
990 08 (ꢁ90)c
PO(OH)2
F
F
11 04
35 07
38 08
PO(OH)2
F
F
SONH2
F
F
SONH2
F
a
Enzymatic assay was carried out in 96-well plates. The initial rate of PTPase-catalyzed hydrolysis of pNPP was measured at
405 nm. IC50 value was determined under fixed pNPP concentration of 1 mM (n = 3; represents Mean SD).
b
Selected test compounds which were screened for TCPTP inhibitory activity also showed >5000-fold selectivity over CD45,
LAR, SHP-1 and SHP-2 enzymes (data not shown).
c
Fold selectivity calculated as ratio of average IC50 values of TCPTP/PTP1B inhibitions.
nyl templates (5k–l) showed better PTP1B inhibitory activity com-
pare to its bioisostere DFMS-substituted templates (5m–n). At pH
6.5 (simulate with in vitro system), it has been reported that the
monoanionic DFMP exhibit an equilibrium with its dianionic form
and the PTP1B enzyme show strong binding interaction with the
dianionic form.22 Thus compounds containing DFMP-substituted
templates (5k–l) showed better PTP1B inhibitory activity compare
to DFMS-substituted templates (5m–n), may be due to the prefer-
ence of PTP1B enzyme binding with the dianionic form of DFMP. In
second set, replacement of bromo analogues (5k–n) with its more
electronegative fluoro analogues (5o–r), leads to a highly potent
PTP1B inhibitors among all series. As observed in the previous
series, electronegative fluoro analogues (5o–r) were found to be
more potent compare to its bromo analogues (5k–n), which could

D. Patel et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1111–1117
1115
be due to increase in the electronegativity and decrease in the
steric bulk (5k–n: ortho-bromo vs 5o–r: ortho-fluoro) adjacent
to the DFMS/DFMP groups.
DFMP/DFMS-substituted naphthyl/quinolinyl templates at R1,
showed excellent selectivity over TCPTP, indicated that among
the two different ring systems (benzyl/fused-ring system) selected
as R1, only fused-ring templates (naphthyl/quinolinyl derivatives)
showed best selectivity. The in vitro PTP1B inhibitory activity
and PTPs selectivity was also determined for standard compound
2 (Table 1; IC50: 78 02 nM, with ꢁ7-fold selectivity over TCPTP)
and the IC50 values (PTP 1B inhibitory activity) were found to be
in agreement with the literature (IC50: 74 nM).18
The in vivo antidiabetic activity of the most potent and selective
compounds (5o and 5p; @ 20 mpk, po) was evaluated in male C57BL/
6J mice, using IPGTT (Intraperitoneal glucose tolerance test) proto-
col and changes in serum glucose levels (AUC glucose @ 240 min;
mg dLꢀ1), with compounds 5o and 5p are shown in Figure 2.20 Com-
pound 5o showed excellent antidiabetic activity orally, whereas
compound 5p showed moderate activity upon oral administration
(ꢀ52.8 5.36 and ꢀ19.18 5.8, respectively). In vivo antidiabetic
activity was also evaluated for standard compound 2 (as positive
control). Compared to vehicle control, there was no change in the
serum glucose levels (AUC glucose) was observed with compound
2, when it was administered @ 20 mpk, po. Compound 2 was found
to be inactive, which could be due to its poor oral bioavailability.
Further to understand the pharmacokinetic (PK) profile, a com-
parative single dose (20 mgkgꢀ1 iv or po) study of 5o and 5p was
carried out in male C57BL/6J mice (n = 6) and the various PK
parameters such as Tmax, t1/2, Cmax, AUC and %F were calculated
and recorded (Table 3).21 In a single-dose PK study, compound
5o showed rapid tmax, good area under the curve (AUC), and ex-
tended half-life (t1/2), whereas 5p showed extended tmax, short t1/
2 and moderate AUC. Relative to 5p, compound 5o showed ꢁ7-fold
The SAR study reveals that the para-substituted pTyr mimetics
exhibit favorable PTP1B inhibitory activity. The compounds with
ortho-halogen substitution next to pTyr mimetics showed potent
PTP1B inhibitory activity and among three-different pTyr mimet-
ics, DFMP exhibited the highest PTP1B inhibitory activity. Simi-
larly, the fluoro analogues of naphthyl/quinolinyl templates
containing DFMP as a pTyr mimic were found to be more potent
than their corresponding bromo analogues. Among two series
tested, compounds with DFMP/DFMS-substituted naphthyl/quin-
olinyl templates (5k–r; second series) were found to be more
potent than the benzyl derivatives (5a–j; first series). One possible
explanation for this is that naphthyl/quinolinyl ring possibly
involves more pi-stacking interactions with aromatic residues lo-
cated close to the active site of PTP1B, compare to benzyl ring.
Overall, in vitro PTP1B inhibitory activity results clearly suggest
that the potency of triaryl sulfonamide-based PTP1B inhibitors
can be modulated using suitable substitutents at R1 position.
The in vitro selectivity over PTPs (PTPa, LAR, CD45, VHR, SHP-1,
SHP-2 and TCPTP) was evaluated for most potent compounds (5a,
5c, 5f, 5o and 5p), using p-NPP assay and IC50 values are listed in
(Tables 1 and 2).19 Compounds 5a and 5c showed ꢁ15 to 25-fold
selectivity, 5f showed ꢁ20-fold selectivity, 5o and 5p showed
ꢁ90 to 96-fold selectivity over TCPTP enzyme, while all the
selected test compounds showed >5,000-fold selectivity over PTPa,
LAR, CD45, VHR, SHP-1 and SHP-2 enzymes. The compounds 5a, 5c
and 5f containing R1 as DFMP/DFMS-substituted benzyl groups
showed poor selectivity. Compounds 5o and 5p containing
40000
30000
20000
10000
0
$
*
*P<0.05, $P<0.01, Two-Way ANOVA followed by Bonferroni post test, M SEM;
Standard compound 2 was also tested @ 20 mpk, po, but no change in the AUC glucose was observed with respect to
vehicle control.
Figure 2. In vivo antidiabetic activity of compounds 5o and 5p in C57 mice (IPGTT).
Table 3
Pharmacokinetic (PK) study parametersa of compounds 5o and 5p
Compd No.
Tmax (h)
Cmax
(lg/ml)
T1/2 (h)
AUC (0–1) h
lg/ml
%Fb
5o
5p
0.31 0.01
0.69 0.10
6.3 0.51
0.96 0.32
6.96 0.91
0.99 0.76
8.91 0.14
1.32 0.31
6.51
0.9
a
In male C57BL/6 J mice (n = 6), compounds 5o and 5p were administered orally (po) at 20 mgkgꢀ1 dose and plasma concentration was analyzed by LC–MS, values indicate
Mean SD.
b
Oral bioavailability (%F) was calculated wrt to iv AUC (5o: 137.07 4.28 and 5p: 146.66 9.81 h l
g/ml) administered at 20 mgkgꢀ1 dose, iv.

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D. Patel et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1111–1117
Figure 3. Key interaction of compounds 2 and 5o with active site-A and secondary aryl-binding site-B. (a) Binding pose of compound 2 in the PTP1B active site is indicated,
wherein it interact closely with key residues of site A and marginally with site B. (b) Compound 5o docks very well into both the sites (A & B), particularly, flipping of
thiadiazolyl moiety in site B and its strong interactions with key resides of site B (Asp548, Arg524 and Arg754) favors best fits of 5o. Residue numbering is as per current
numbering (PDB code: 1Q6T): Arg24 (524), Asp48 (548) and Arg254 (754).
higher bioavailability (%F: ꢁ6.5%). Thus improved pharmacokinetic
profile of compound 5o justifies its excellent pharmacodynamic ef-
fects (antidiabetic activity) in C57 mice, when administered orally.
The molecular docking analysis of 5o was carried in Glide, to
understand its critical interactions with both the binding sites (A
and B) of PTP1B enzyme.23 The initial Glide docking studies for
5o gave poor results in terms of binding conformation. Based on
this observation, the compound 5o was docked using the induced
fit docking (IFD) protocol. The IFD is based on the docking program
Glide with the refinement module in Prime (Schrodinger, Inc.),
which was reported to accurately predict the ligand binding modes
and concomitant structural changes in the receptor.23
derivatives shows best selectivity, due to favorable orientation of
ligand across both the binding sites of the PTP1B enzyme. The lead
compound 5o shows significant antihyperglycemic effects
(in vivo), along with oral bioavailability. Thus, preliminary study
results confirm that highly potent and selective PTP1B inhibitor
could be viable approach for the effective treatment of T2DM.
Acknowledgment
We are grateful to the management of Zydus Group for encour-
agement and support.
Since the interaction of compound 2 with the PTP1B enzyme is
unpublished, molecular docking analysis was also carried out for
compound 2 (Fig. 3a). As described earlier, for achieving selectivity
over TCPTP, interactions in site B is essential. The IFD results illus-
trate that compound 2 completely docks in the binding site A and
the DFMP substituted phenyl ring of compound 2 strongly coordi-
nate with Phe682 (site A residue), while the oxy acetic acid and thi-
adiazolyl ring of compound 2 partially project in site B and interact
partly with key residues of site B. In vitro, ꢁ7-fold selectivity over
TCPTP enzyme was observed with compound 2 and it could be
attributed to its partial orientation in site B, which is essential
for achieving selectivity over TCPTP enzyme.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.11.122.
References and notes
1. Bloomgarden, Z. T. Diabetes Care 1996, 19, 295.
2. Wild, S.; Roglic, G.; Green, A.; Sicree, R.; King, H. Diabetes Care 2004, 27, 1047.
3. Eckel, R. H.; Grundy, S. M.; Zimmet, P. Z. Lancet 2005, 365, 1415.
4. Hussain, A.; Claussen, B.; Ramachandean, A.; Williams, R. Diabetes Res. Clin.
Pract. 2007, 76, 317.
5. (a) Nathan, D. M. N. Engl. J. Med. 2002, 347, 1342; (b) Ceriello, A. Diabetes 2005,
54, 1.
The IFD results of compound 5o illustrated that introduction of
DFMP-naphthyl template allows to adopt new conformation; as a
result, it docks very well at the both binding sites ( Fig. 3b). It
was observed that upon IFD, flipping of thiadiazolyl ring was ob-
served in site B and because of this change, compound 5o docks
very well into both the sites (A and B). Thus the PTP1B selectivity
over TCPTP was achieved by taking advantage of amino acid differ-
ences in the site B. In particular, the flipping of thiadiazolyl moiety
in site B and its strong interaction with key resides of site B
(Asp548, Arg524 and Arg754). The favorable hydrogen bond inter-
actions of compound 5o with both the sites (A and B) of PTP1B en-
zyme support its potent in vitro PTP1B activity and excellent
selectivity over TCPTP.
6. Nichols, G. A.; Gomez-Caminero, A. Diabetes Obes. Metab. 2007, 9, 96.
7. Westphal, S. A.; Palumbo, P. J. Insulin 2007, 2, 31.
8. (a) Frank, L. JAOA 2010, 110, eS13; (b) Krentz, A. J.; Bailey, C. J. Drugs 2005, 65.
9. Padwal, R.; Majumdar, S. R.; Johnson, J. A.; Varney, J.; McAlister, F. A. A. Diabetes
Care 2005, 28, 736.
10. (a) Vague, P.; Raccah, D. Horm. Res. 1992, 38, 28; (b) Taylor, S. I.; Accili, D.; Imai,
Y. Diabetes 1994, 43, 735.
11. Cho, S. Y.; Ahn, J. H.; Ha, J. D.; Kang, S. K.; Baek, J. Y.; Han, S. S.; Shin, E. Y.; Kim, S.
S.; Kim, K. R.; Cheon, H. G.; Choi, J.-K. Bull. Korean Chem. Soc. 2003, 24, 1455.
12. Pei, Z.; Liu, G.; Lubben, T. H.; Szczepankiewicz, B. Z. Curr. Pharm. Des. 2004, 10.
13. Puius, Y. A.; Zhao, Y.; Sullivan, M.; Lawrence, D. S.; Almo, S. C.; Zhang, Z.-Y. Proc.
Natl. Acad. Sci. U.S.A. 1997, 94, 13420.
14. Anderson, H. S.; Iversen, L. F.; Jeppesen, C. B.; Branner, S.; Norris, K.;
Rasmussen, H. B.; Moller, K. B.; Moller, N. P. H. J. Biol. Chem. 2000, 275, 7101.
15. Burke, T. R., Jr.; Ye, B.; Akamatsu, M.; Ford, H.; Yan, X.; Kole, H. K.; Wolf, G.;
Shoelson, S. E.; Roller, P. P. J. Med. Chem. 1996, 39, 1021.
16. Combs, A. P. J. Med. Chem. 2010, 53, 2333.
In summary, novel triaryl sulfonamide-based PTP1B inhibitors
containing DFMP-substituted naphthyl template at R1 show excel-
lent in vitro potency and selectivity over TCPTP, indicating that
among three different ring systems selected as R1, only naphthyl
17. Patel, D.; Jain, M.; Shah, S. R.; Bahekar, R.; Jadav, P.; Darji, B.; Siriki, Y.;
Bandyopadhyay, D.; Joharapurkar, A.; Kshirasagar, S.; Patel, H.; Shaikh, M.;
Sairam, K. V. V. M.; Patel, P. ChemMedChem 2011, 6, 1011.
18. (a) Han, Y.; Belley, M.; Bayly, C. I.; Colucci, J.; Dufresne, C.; Giroux, A.; Lau, C. K.;
Leblanc, Y.; Mckay, D.; Therien, M.; Wilson, M.; Skorey, K.; Chan, C.; Scapin, G.;

D. Patel et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1111–1117
1117
Kennedy, B. P. Bioorg. Med. Chem. Lett. 2008, 18, 3200; (b) Holmes, C. P.; Li, X.;
Pan, Y.; Xu, C.; Bhandari, A.; Moody, C. M.; Miguel, J. A.; Ferla, S. W.; De
Francisco, M. N.; Frederick, B. T.; Zhou, S.; Macher, N.; Jang, L.; Irvine, J. D.;
Grove, J. R. Bioorg. Med. Chem. Lett. 2005, 15, 4336; (c) Holmes, C. P.; Li, X.; Pan,
Y.; Xu, C.; Bhandari, A.; Moody, C. M.; Migule, A. J.; Ferla, S. W.; De Francisco, M.
N.; Frederick, B. T.; Zhou, S.; Macher, N.; Jang, L.; Irvine, J. D.; Grove, J. R. Bioorg.
Med. Chem. Lett. 2008, 18, 2719.
POD method (Ranbaxy Fine Chemicals Limited, Diagnostic division, India),
using Spectramax-190, in 96-microwell plate reader (Molecular devices
Corporation, Sunnyvale, California). Mean values of duplicate samples were
calculated using Microsoft excel and the Graph Pad Prism software (Ver 4.0)
was used to plot a area under the curve (0–240 min AUC). The AUC obtained
from graphs were analyzed for two-way ANOVA, followed by Bonferroni post
test, using Graph Pad prism software.
19. Moretto, A. F.; Kirincich, S. J.; Xu, W. X.; Smith, M. J.; Wan, Z.-K.; Wilson, D. P.;
Follows, B. C.; Binnun, E.; Joseph-McCarthy, D.; Foreman, K.; Erbe, D. V.; Zhang,
Y.-L.; Tam, S. K.; Tam, S. Y.; Lee, J. Bioorg. Med. Chem. 2006, 14, 2162.
21. Briefly, for single dose PK study, test compounds were administered orally/iv
on a body weight basis (20 mgkgꢀ1) to overnight fasted male C57BL/6J mice.
Serial blood samples were collected in microcentrifuge tubes containing EDTA
at pre-dose, 0.15, 0.3, 0.5, 0.75, 1, 2, 4, 6, 8, 24 and 30 h post-dose after
compounds administration. Approximately 0.3 ml of blood was collected at
each time point and centrifuged at 4 °C. The obtained plasma was frozen,
stored at ꢀ70 °C and the concentrations of compounds in plasma were
determined by the LC–MS/MS (Shimadzu LC10AD, USA), using YMC
20. (a) Chen, D.; Wang, M. Diabetes Obes. Metab. 2005, 7, 307; (b) Kim, J. G.; Baggio,
L. L.; Bridon, D. P.; Castaigne, J. P.; Robitaille, M. F.; Jette, L.; Benquet, C.;
Drucker, D. J. Diabetes 2003, 52, 751; (c) Study was conducted in male C57BL/6J
mice, using IPGTT protocol (age 8–12 weeks; Wt: ꢁ20–25 g) and animal
experiments were conducted according to the internationally valid guidelines
following approval by the ‘Zydus Research Center Animal Ethical Committee’.
Two days prior to the study, the animals were randomized and divided into 2
groups (n = 6), based upon their fed glucose levels. Animals were left for 2 days
under acclimatization and maintained on a standard diet. On the day of
experiment, food was withdrawn from all the cages, water was given ad-
libitum and were kept for overnight fasting. Briefly, overnight fasted mice were
dosed orally (po) with the test compounds 5o or 5p (20 mg/kg), 0.5 h prior to
the intraperitoneal (ip) glucose load (1.5 g/kg). Blood samples were collected at
various time points (0, 30, 60, 120 and 240 min). Blood samples were
centrifuged and the separated serum was immediately subjected for the
glucose estimation. The glucose estimation was carried out with DPEC-GOD/
hydrosphere C18 (2.0 ꢂ 50 mm,
3
l
m) column (YMC Inc., USA). The
t1/2 Cmax AUC and %F were
pharmacokinetic parameters, such as Tmax
,
,
,
calculated using a non-compartmental model of WinNonlin software version
5.2.
22. (a) Chen, L.; Wu, L.; Otaka, A.; Smyth, M. S.; Roller, P. R.; Burke, T. R.; den
Hertog, J.; Zhang, Z.-Y. Biochem. Biophys. Res. Commum. 1995, 216, 976; (b)
Burke, T. R.; Ye, B.; Yan, X.; Wang, S.; Jia, C.; Grzyb, J.; Liu, S.; Hum, G.; Taylor, S.
D. Biochemistry 1996, 35, 15898.
23. Schrodinger Suite 2010, Glide version 5.6, Prime version 2.2; Schrodinger, LLC:
New York, 2010.