Discovery and structure-activity relationships of novel sulfonamides as potent PTP1B inhibitors

Article abstract of DOI:10.1016/j.bmcl.2005.06.061

A series of novel sulfonamides containing a single difluoromethylene- phosphonate group were discovered to be potent inhibitors of protein tyrosine phosphatase 1B. Structure-activity relationships around the scaffold were investigated, leading to the identification of compounds with IC₅₀ or K_i values in the low nanomolar range. These sulfonamide-based inhibitors exhibit 100 and 30 times higher inhibitory activity than the corresponding tertiary amines and carboxamides, respectively.

Full text of DOI:10.1016/j.bmcl.2005.06.061

Bioorganic & Medicinal Chemistry Letters 15 (2005) 4336–4341
Discovery and structure–activity relationships of novel
sulfonamides as potent PTP1B inhibitors
Christopher P. Holmes,* Xianfeng Li, Yijun Pan, Caiding Xu, Ashok Bhandari,
Claire M. Moody, Joy A. Miguel, Steven W. Ferla, M. Nuria De Francisco,
Brian T. Frederick, Siqun Zhou, Natalie Macher, Larry Jang, Jennifer D. Irvine and
J. Russell Grove
Affymax, Inc., 4001 Miranda Avenue, Palo Alto, CA 94304, USA
Received 24 May 2005; revised 11 June 2005; accepted 13 June 2005
Available online 19 July 2005
Abstract—A series of novel sulfonamides containing a single difluoromethylene-phosphonate group were discovered to be potent
inhibitors of protein tyrosine phosphatase 1B. Structure–activity relationships around the scaffold were investigated, leading to
the identification of compounds with IC50 or Ki values in the low nanomolar range. These sulfonamide-based inhibitors exhibit
100 and 30 times higher inhibitory activity than the corresponding tertiary amines and carboxamides, respectively.
Ó 2005 Elsevier Ltd. All rights reserved.
Protein tyrosine phosphatase 1B (PTP1B), an intra-
cellular non-receptor PTPase, plays an essential role in
the regulation of insulin signaling pathway by dephos-
phorylating the activated insulin receptor.1 Recent
knock-out studies have demonstrated that PTP1B-defi-
cient mice display enhanced insulin sensitivity and resis-
tance to diet-induced obesity.2,3 Furthermore, diabetic
mice treated with a specific PTP1B antisense oligonu-
cleotide exhibit normalization of blood glucose level
and improvement in insulin sensitivity.4 Therefore, there
has been tremendous interest in the development of
PTP1B inhibitors that would provide novel therapeutic
agents in treating Type II diabetes and obesity.5
both the Taylor and Zhang groups extended this ap-
proach by identifying a series of compounds bearing
two DFMP groups as potent PTP1B inhibitors.7,8 These
bis-phosphonates exhibit much higher potency by bind-
ing to both the catalytic site and the second phosphate
binding site of the enzyme resulting from its complemen-
tarity with the tandem pTyr1162 and pTyr1163 groups of
the natural substrate.9 However, introduction of an
additional phosphonate group in the molecule is likely
to have a negative impact on cell permeability and oral
bioavailability, which will be key attributes of any suc-
cessful drug against this class of enzymes.
Numerous small molecules have been described over the
last few years with activity against PTP1B. These in-
clude triaryl compounds from Merck Frosst,10 oxalyl-
arylaminobenzoic acids from Abbott,11 numerous
compounds from Pharmacia,12 hundreds of compounds
from Wyeth–Ayerst,13 2-oxalylaminobenzoic acids from
Novo Nordisk,14 a-ketoacids from Seto,15 aminothiaz-
oles from Wipf,16 and formylchromanes from Cho.17
We have recently reported the discovery of a series of
a,a-difluoro-b-ketophosphonates as low micromolar
PTP1B inhibitors.18 For example, sulfonamide 1 was
shown to inhibit PTP1B with an IC50 of 12 lM. During
the course of our studies, we found that replacement of
a,a-difluoro-b-ketophosphonate with a DFMP moiety
gave a slightly more active compound 2 with an IC50
An effective strategy for designing PTP1B inhibitors has
focused on the incorporation of non-hydrolyzable phos-
photyrosine (pTyr) mimetics in appropriate peptide
substrates or small molecule scaffolds. Among these,
a,a-difluoromethylenephosphonic acids (DFMP) are
especially effective in obtaining potent small molecule
inhibitors of PTP1B. Burke et al.6 first reported that
simple aromatics containing one DFMP group are
weak, competitive inhibitors of PTP1B. Subsequently,
Keywords: PTP1B inhibitors; Sulfonamides.
*
Corresponding author. Tel.: +1 650 812 8737; fax: +1 650 424
0832; e-mail: chris_holmes@affymax.com
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.06.061

C. P. Holmes et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4336–4341
4337
of 7 lM. Both 1 and 2 contain a sulfonamide scaffold,
which represents a good starting point for further opti-
mization. Sulfonamides are known to function as good
hydrogen bond acceptors in many biological systems,
and more importantly, they are common features of
many known drugs. Given the easy synthesis and avail-
ability of large number of building blocks, our approach
was to make analogs in a parallel fashion to maximize
interactions with PTP1B. In this paper, we report our
optimization of 2 by introducing substitutions in all
three aryl rings as well as altering the sulfonamide back-
bone (Fig. 1).
The general method for the synthesis of sulfonamides
3–30 is shown in Scheme 1. Bromination of 4-methyl dif-
luoromethylenephosphonate diethylesters (R1@H, OMe,
Br) with NBS in carbon tetrachloride in the presence of
benzoyl peroxide gave the benzylbromide intermediates.
Mono-substituted sulfonamides were prepared by react-
ing benzenesulfonyl chlorides with primary amines. For
those benzenesulfonylchlorides that are not commercially
available, they were prepared by reaction of the substitut-
ed benzenes with chlorosulfonic acid according to the lit-
erature.19 Alkylation of the mono-substituted
sulfonamides with 4-bromomethyl phosphonates gave
the di-substituted sulfonamides, which were subsequently
converted to products 3–30 by treatment with TFA and
TMSBr to hydrolyze the t-butyl esters and the phospho-
nate diethylesters. The desired phosphonic acids were
isolated by preparative HPLC and their molecular com-
position was confirmed by ESI-MS.
The inhibitory activity against PTP1B was evaluated by
our previous described method using O-methyl fluores-
cein monophosphate (OMFP) as a substrate.18 IC50
values are shown in Tables 1 and 2. For representative
Figure 1.
Scheme 1. Reagents and conditions: (a) NBS/Bz2O2, hm, CCl4; (b) R2ArCH2NH2, Et3N, CH2Cl2; (c) BrCH2R1C6H3CF2PO(OEt)2, K2CO3, CH3CN,
70 °C; (d) when R3 contains CO2tBu, 50% CF3CO2H in CH2Cl2; (e) TMSBr, CH2Cl2, then H2O.
Table 1. Effects of acidic groups in C-ring on inhibition of PTP1B
Compound
R1
R2
R3
R4
IC50 (lM)a
Ki (lM)
3
4
H
H
H
H
H
H
H
H
H
H
H
H
H
H
F
4.2
0.6
3.0
3.0
4.0
1.0
4.0
5.0
4.0
1.9
2.9
1.6
H
OCH2COOH
OCH2COOH
OCH2COOH
OCH2COOH
OCH2COOH
OCH2COOH
OCH2COOH
OCH2COOH
OCH2COOH
OH
H
1.1
5
F
Cl
H
6
H
7
Br
F
H
8
F
9
CF3
OCF3
CH3
CH3
H
H
10
11
12
13
14
H
H
CH3
COOH
OCH2COOH
H
F
a PTP1B assays were conducted as previously reported in Ref. 18. Values are means of duplicate experiments.

4338
C. P. Holmes et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4336–4341
Table 2. Effects of substitutions of R1–R3 on inhibition of PTP1B
Compound
R1
H
R2
R3
IC50 (lM)a
Ki (lM)
15
OCH2COOH
0.77
16
17
18
H
H
H
OCH2COOH
OCH2COOH
OCH2COOH
0.63
1.1
0.6
0.59
19
20
H
H
OCH2COOH
OCH2COOH
1.0
0.18
21
22
23
24
H
H
H
H
OCH2COOH
OCH2COOH
OCH2COOH
OCH2COOH
0.074
0.22
9.0
0.056
6.8
25
26
27
28
29
30
H
H
0.21
0.098
0.053
Br
OCH2COOH
OCH2COOH
OCH2COOH
OCH2COOH
OCH2COOH
0.035
0.060
0.028
1.1
OCH3
Br
0.013
0.014
OCH3
Br
0.031
a PTP1B assays were conducted as previously reported in Ref. 18. Values are means of duplicate experiments.
compounds, inhibition kinetics was also determined and
Ki values are given in Tables 1 and 2.
focused on converting either the B or C aryl rings to a
phenoxyacetic acid to explore if binding with the non-
catalytic binding site of PTP1B could be enhanced.9,20
Early work indicated that incorporation of the acidic
group in the B-ring does not improve inhibitor potency
(data not shown), whereas incorporation of an acid in
The sulfonamide scaffold, with three readily available
groups, allows one to readily explore structure–activity
relationships in three directions. Our initial efforts

C. P. Holmes et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4336–4341
4339
the C-ring, however, led to more active compounds. As
shown in Table 1, 4 containing an acid in the para posi-
tion of the C-ring showed a sevenfold improvement in
potency compared to 3. This compound inhibited
PTP1B with an IC50 of 0.6 lM and is a competitive
inhibitor with a Ki of 1.1 lM. Subsequently, several sub-
stituents were introduced into the C-ring of 3 to further
probe interactions with the enzyme. All these attempts
(5–14), however, resulted in slightly decreased activity.
It is interesting that both 8 and 14 exhibit the same affin-
ity to the enzyme with the acidic side chain in either the
para or meta position, suggesting that the binding pock-
et for the phenoxyacetic acid group of the C-ring is not
overly limited.
replacements of the sulfonamide linking the three aryl
rings. Scheme 2 shows the synthesis of 31, which is the
tertiary amine analog of 18. Reaction of benzylmethyl-
amine with Boc-Gly-OH followed by deprotection of
the Boc group gave N-methyl-N-benzyl glycine amide.
Subsequent reductive amination with OHC–C6H4–
OCH2- CO2tBu afforded the corresponding secondary
amine. Alkylation of the secondary amine with 4-bro-
momethyl diethyl-phenylphosphonate and treatment
with TFA and TMSBr gave tertiary amine 31. Com-
pound 31, however, proved to be a poor inhibitor with
an IC50 of 67.5 lM. Hence, the replacement of SO2 with
CH2 resulted in 100-fold decrease in potency, indicating
that the sulfonamide does more than simply serving as a
linker for the three aryl groups. The poor activity of the
tertiary amine 31 is in contrast to the results observed by
workers at Novo Nordisk in their 2-oxalylaminobenzoic
acid series,14b where distal amino groups enhanced
activity against PTP1B.
After the identification of 4, a large number of new
analogs were synthesized to explore substitutions in
the B-ring on PTP1B activity. Representative exam-
ples (15–30) from this set of compounds are shown in
Table 2.
Shown in Scheme 3 is the synthesis of 36, which is the
carboxamide analog of sulfonamide 21. The key step is
the preparation of 4-formyl DFMP by a Sommelet reac-
tion. Reductive amination of this aldehyde with 4-(1,2,3-
thiadiazol-4-yl)benzylamine gave secondary amine 32.
The coupling of 32 with 4-hydroxybenzoic acid gave
carboxyamide 34. Subsequent alkylation of 34 with t-
butyl bromoacetate followed by TFA and TMSBr treat-
ment afforded 36. Both 32 and 34 were deprotected to
afford 33 and 35 for biological evaluation. The SAR is
again very strong in this series, with 35 containing a
4-hydroxybenzoic acid group showing twofold better
activity than 33, and conversion of the phenol to a phe-
noxyacetic acid group to form 36 further improving
activity by another threefold. Compound 36 inhibited
PTP1B with an IC50 of 2.3 lM, which is 30-fold less po-
tent than 21, yet is still 30-fold better than 31. Discount-
ing the absence of the beneficial thiadiazole ring in 31
(enhancing activity up to eightfold in 18 ! 21), it is
tempting to postulate that the superior H-bond accept-
ing properties of the sulfonamide over the carboxamide
and tertiary amines of 36 and 31, respectively, accounts
for the better activity of 21. In addition, the sulfonamide
framework may display a subtly different three-dimen-
sional orientation than the carboxamide or tertiary
Replacement of the benzyl ring of 4 by aliphatic chains
lacking an aromatic group resulted in dramatic decreas-
es in activity (23 and 24), suggesting that an aromatic
ring is required for tight binding. Extending the distance
between the sulfonamide and the B-ring aromatic group
by inserting an amide group (18) did not alter the poten-
cy, suggesting that the enzyme binding pocket is fairly
large; in agreement with this, both para or meta substit-
uents on the B-ring aromatic group were well tolerated
(15–17). The most effective substitution was a para
thiadiazole group in the phenyl ring, the introduction
of which resulted in a 10-fold improvement in potency.
Thus, 21 is a potent PTP1B inhibitor with an IC50 of
0.074 lM and a Ki of 0.056 lM. Removing the benzylic
carbon atom to make anilinosulfonamide 22 resulted in
a threefold loss in activity. Of particular note is com-
pound 25 displaying a Ki of 0.098 lM (IC50 0.21 lM),
despite having lost the acidic side chain considered to
be important for activity.
As the DFMP moiety in these compounds presumably
provides the critical interactions with the enzyme, we
investigated substitutions on the aryl ring bearing the
DFMP group. Introduction of a methoxy group next
to the DFMP group showed no beneficial effect on
inhibitory activity (compounds 27 and 29). Introduction
of a bromine atom into 21 afforded 26 with twofold bet-
ter binding, but identical inhibitory activity (i.e., Ki val-
ues are the same). When a bromine atom was introduced
in less active compounds such as 17 or 18, a significant
increase in potency was observed. Thus, both 28 and
30 showed roughly a 40-fold improvement over 17 and
18, and were the most potent PTP1B inhibitors in this
series with Ki values of 0.013 and 0.014 lM, respectively.
These results are consistent with recent results where
introduction of an ortho bromo substituent in a deoxy-
benzoin-based PTP1B inhibitor resulted in 20-fold in-
crease in potency,10a or where a bulky tetrazole could
be accommodated ortho to the phosphate mimetic.12c
Scheme 2. Reagents and conditions: (a) Boc-NHCH2CO2H, EDC,
CH2Cl2; (b) 50% TFA in CH2Cl2; (c) OHC-C6H4-OCH2CO2tBu,
MeOH, then Na(OAc)3BH; (d) BrCH2C6H4CF2PO(OEt)2, K2CO3,
CH3CN, 70 °C; (e) 50% CF3CO2H in CH2Cl2; (f) TMSBr, CH2Cl2,
then H2O.
To further understand the structural requirements for
these inhibitors, we next investigated isosteric

4340
C. P. Holmes et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4336–4341
Scheme 3. Reagents and conditions: (a) C6H12N4, CHCl3, reflux, then 50% AcOH/H2O; (b) thiadiazolyl-C6H4-CH2NH2, MeOH, then Na(OAc)3BH;
(c) HO2C-C6H4-OH, EDCI, CH2Cl2; (d) BrCH2CO2tBu, K2CO3, CH3CN; (e) 50% CF3CO2H in CH2Cl2; (f) TMSBr, CH2Cl2, then H2O.
Koterski, S.; Opgenorth, T. J.; Ulrich, R. G.; Crosby, S.;
Butler, M.; Murray, S. F.; McKay, R. A.; Bhanot, S.;
Monia, B. P.; Jirousek, M. R. Proc. Natl. Acad. Sci. USA
2002, 99, 11357.
amines which provides significant interactions with the
enzyme active site. Previously, sulfonamides have been
used to mimic a water of hydration in the active site
of PTP1B21 or as potential PTyr mimetics22 in the syn-
thesis of PTP1B inhibitors. Finally, it is worth noting
that the series of compounds described here is very selec-
tive against a number of other PTPs including LAR,
VHR, CD45, cdc25, and SHP-2, except the closely relat-
ed TC-PTP.
5. For recent reviews see: (a) Zhang, Z.-Y. Annu. Rev.
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In summary, we have identified potent sulfonamide-
based PTP1B inhibitors containing a single DFMP
group and established the SAR of this class of com-
pounds. Sulfonamide-based inhibitors are 100- and
30-times more potent than the corresponding tertiary
amines and carboxamides, respectively. The presence
of a thiadiazole ring and a DFMP group is sufficient
to afford potent inhibitors of PTP1B, and even more
potent inhibitors result from inclusion of an additional
oxyacetic group into the molecules.
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