PTP1B inhibitors: Synthesis and evaluation of difluoro-methylenephosphonate bioisosteres on a sulfonamide scaffold

Article abstract of DOI:10.1016/j.bmcl.2008.03.007

We have synthesized and evaluated a series of triaryl sulfonamide-based PTP1B inhibitors in which a difluoro-methylenephosphonate group of a potent lead has been replaced by potential bioisosteric replacements. Several mono- or di-charged compounds (8a, 8b, and 15a) were shown exhibit inhibitory activity in the low micromolar range, demonstrating the feasibility of using this approach in identifying non-phosphonate pTyr mimetics in a small molecular scaffold. These results also provide a useful indication of the relative effectiveness of these pTyr mimetics.

Full text of DOI:10.1016/j.bmcl.2008.03.007

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 2719–2724
PTP1B inhibitors: Synthesis and evaluation
of difluoro-methylenephosphonate bioisosteres
on a sulfonamide scaffold
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 19 January 2008; revised 29 February 2008; accepted 3 March 2008
Available online 6 March 2008
Abstract—We have synthesized and evaluated a series of triaryl sulfonamide-based PTP1B inhibitors in which a difluoro-meth-
ylenephosphonate group of a potent lead has been replaced by potential bioisosteric replacements. Several mono- or di-charged
compounds (8a, 8b, and 15a) were shown exhibit inhibitory activity in the low micromolar range, demonstrating the feasibility
of using this approach in identifying non-phosphonate pTyr mimetics in a small molecular scaffold. These results also provide a
useful indication of the relative effectiveness of these pTyr mimetics.
Ó 2008 Elsevier Ltd. All rights reserved.
Recently, there has been tremendous interest in the
development of inhibitors of protein tyrosine phospha-
tase 1B (PTP1B) as therapeutic agents in treating Type
II diabetes and obesity.1 Much of the effort in designing
active site directed PTP1B inhibitors has focused on the
synthesis of phosphotyrosine (pTyr) mimetics, which
serve as non-hydrolyzable replacements for the critical
pTyr residue.2 One of the most effective pTyr mimetics
that has been developed is a,a-difluoro-methylenephos-
phonic acid (DFMP).3,4 The high affinity has been
attributed to the direct hydrogen bonding of fluorines
with enzyme active site residues.5 One limitation of these
inhibitors, however, is their poor cell permeability due
to the dianionic nature of the phosphonate group at
physiological pH, although recent strides have been
made in predicting the activity of PTP1B inhibitors.6
The discovery of effective non-phosphonate pTyr mimet-
ics will facilitate the development of more drug-like
PTP1B inhibitors as therapeutic agents.
charged or monoanionic pTyr mimetics. The replace-
ment of a DFMP moiety in a PTP1B inhibitor by
potential bioisosteric replacements generally leads to
dramatic decreases in binding ability. Previous efforts
have focused on utilizing DFMP-containing high-affin-
ity peptides as display platforms to discover non-phos-
phonate pTyr mimics, which provide starting points
for developing small molecule inhibitors.8–10
We have identified previously a series of triaryl sulfon-
amide based PTP1B inhibitors containing only one sin-
gle DFMP group.11 For example, 1a and 1b are potent
inhibitors of PTP1B with IC50 value of 0.074 lM and
0.20 lM, respectively (Fig. 1). It has been shown that
these bind to the active site in a competitive manner
and also contain optimized substitutions to provide sig-
nificant interactions beyond the pTyr pocket. Therefore,
we sought to use the triaryl sulfonamide as suitable
scaffold to investigate non-phosphonate bioisosteric
replacements while maintaining reasonable PTP1B
inhibitory activity. This paper describes the synthesis
and inhibition activities of a series of sulfonamide ana-
logues, where the DFMP group has been replaced with
potential pTyr mimics with the focus on identifying min-
imally charged compounds that retain potency for the
PTP1B enzyme.
Because of the electrostatic properties of the enzyme
active site,7 it has proven difficult to develop effective un-
Keywords: PTP1B; Phosphatase; Bioisostere; Sulfonamide.
*
Corresponding author. Tel.: +1 650 812 8737; fax: +1 650 424
0832; e-mail: chris_holmes@affymax.com
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.03.007

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C. P. Holmes et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2719–2724
fluorinated analogues3a since fluorine atoms are directly
X
A
S
involved in hydrogen bonding with the amide bond of
the active site residue Phe-182.5 O-Carboxymethyl sali-
cylic acid13 and 2-(oxalyamino)-benzoic acid14 represent
two types of dianionic pTyr mimetics that have been used
in the development of PTP1B inhibitors. Both of these
were found to be acceptable when appended to the triaryl
sulfonamide scaffold, resulting in low micromolar IC50
values for 10a, 10b, 15a, and 15b. The final dianionic ana-
logue 23a turned out to be a very weak inhibitor of the en-
zyme (IC50 = 74 lM).
O
O
N
O
P
C
OH
OH
B
F
F
S
N
N
1a, X = OCH2COOH, IC50 = 0.074 μM
1b, X = H, IC50 = 0.20 μM
Replacement of the DFMP group with a simple mono-
charged oxo-acetic acid gave 3a and 3b, which showed
IC50 values of 59.6 and 54.1 lM, respectively. These re-
sults were encouraging considering that the oxo-acetic
acid contains only one charge and can be used as a
starting point to make additional modification to
improve the binding ability. Subsequently, fluorine
atoms were introduced in the methylene group to gen-
erate 4a and 4b, which showed improved affinity, and
not surprisingly, the para position of the aromatic
group was better than the meta position (5a and5b
are roughly 5-fold worse than 4a and 4b). Introduction
of substituents into the one or more of the ortho posi-
tions of the aryl ring can significantly influence the
binding to PTP1B. Thus, the bromo derivatives 8a
and 8b are remarkably potent relative to the parent
ring found in 3a and 3b, as we11 and others have
observed.14 It is likely that bromo substitution in the
ortho position of a pTyr mimetic provides a hydropho-
bic interaction with the enzyme active site. It has been
shown from X-ray studies of co-crystal complexes that
a hydrophobic pocket exists at the vicinity of the cata-
lytic site.15 Other substituents such as difluoro (6a and
6b), chloro (7a and 7b), and methyl (9a and 9b) were
tolerated, but do not seem to offer any advantage,
which is in clear contrast to trends observed by others
in the thiophene series of PTP1B inhibitors.16 We had
hoped that the fluorine atoms of 6 would be close en-
ough to interact with PTP1B and compensate for the
single charge of the mimetic, but this turned out not
to be true. Attempting to capitalize on this ‘‘bromo ef-
fect’’, we combined the fluorines of 4 with the bromine
of 8 to prepare hybrid compounds 21a and 21b, but
were unable to achieve any synergistic potency; in fact
the addition of fluorines to compounds 8a and 8b
resulted in significantly worse binding to the enzyme.
Figure 1. Structures of DFMP sulfonamide leads.
True to the definition of a versatile scaffold, the triaryl
sulfonamides (see Table 1) could be made by a variety
of techniques, as shown in Schemes 1 and 2, depending
on the availability of the appropriate reagents. Method
A (Scheme 1) involved joining the A–B rings first, fol-
lowed by a reaction with an electrophilic bromoben-
zyl-C ring protected pTyr mimetic to form the ABC
triaryl sulfonamide. Typically, the pTyr mimetic is liber-
ated through either methyl/ethyl ester saponification
with base or tert-butyl ester cleavage with TFA. In
Method B, the B–C rings are first joined by the reaction
of a sulfonylchloride A ring with an aminobenzyl C ring
protected pTyr mimetic, followed by the reaction with
thiadiazolylbenzylbromide and subsequent pTyr mi-
metic generation with again either base or acid-induced
ester cleavage. Method C (Scheme 2) involved forming
the B–C ring bonds first through a reduction amination
of the C-ring protected pTyr mimetic benzaldehyde with
thiadiazolylbenzylamine, followed by the reaction with
the A-ring sulfonylchloride to form the triaryl scaffold.
The substituted benzylamines, benzylaldehydes, and sul-
fonylchlorides were either commercially available or
formed from straightforward literature procedures.
The desired products were isolated as acids by prepara-
tive RP-HPLC, their purity assessed by RP-HPLC, and
their molecular composition 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.12 IC50 val-
ues are shown in Table 1. The compounds are divided
into two series. Series I includes analogues which are
based on the parent compound 1a, where X represents
oxoacetic acid. In Series II, the compounds are the cor-
responding analogues based on 1b lacking the acid
(X = H). Of the various DFMP replacements examined,
4 were dianionic at physiologic pH as is DFMP, while
20 contained a single acidic group.
When situated in these triaryl sulfonamide scaffolds, a
bromine and carboxylic acid appear equally tolerated
by PTP1B. Thus, in both the oxoacetic acid series repre-
sented by compounds 8 and 10, and the 2-(oxalyamino)-
benzoic acid series represented by compounds 15 and
16b, the activities across the same A-ring series are
almost identical. The use of mono-charged pTyr mimet-
ics (i.e., bromo analogues) would presumably have
greater beneficial effect on their cell permeability and
perhaps make up for the large increase in molecular
weight associated with the bromine atom.
Of the dianionic replacements evaluated, non-fluorinated
methylenephosphonate group of 2a and 2b are the most
similar to DFMP, however, only weak inhibition was ob-
tained (IC50 ꢀ 110 lM), indicating the significant role
that the fluorine atoms play in DFMP). The observation
is consistent with previous reports that the DFMP ana-
logues are 1000-times more potent inhibitors than non-
Substituting sulfur for oxygen of the oxoacetic acid
resulted in decreased PTP1B activity (IC50s for 11a

C. P. Holmes et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2719–2724
2721
Table 1. In vitro activity of pTyr mimics against PTP1Ba
X
O
O
S
N
S
N
N
Compound
pTyr mimetics
Synthesis method
A
X
IC50 (lM)
O
P
OH
OH
1a
1b
OCH2CO2H
H
0.074
0.20
F
F
O
P
2a
2b
C
A
OCH2CO2H
H
96.8
123
OH
OH
3a
3b
OCH2CO2H
H
59.6
54.1
OH
O
O
F
F
4a
4b
A
A
A
A
A
A
A
A
OCH2CO2H
H
29.1
97.1
OH
O
O
O
O
5a
5b
OCH2CO2H
H
230
198
OH
F
F
F
6a
6b
OCH2CO2H
H
19.9
137
OH
O
F
O
7a
7b
OCH2CO2H
H
57.7
53.8
OH
O
Cl
O
8a
8b
OCH2CO2H
H
4.1
7.9
OH
O
O
Br
9a
9b
OCH2CO2H
H
76.2
80.7
OH
O
O
OH
OH
10a
10b
OCH2CO2H
H
4.4
O
12.2
O
O
O
OH
11a
11b
OCH2CO2H
H
114
115
S
(continued on next page)

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C. P. Holmes et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2719–2724
Table 1 (continued)
Compound
pTyr mimetics
Synthesis method
X
IC50 (lM)
12a
12b
Ab
OCH2CO2H
H
>250
173
OH
S
O
O
O
13a
13b
Ab
OCH2CO2H
H
>250
232
OH
S
O
O
OH
14a
14b
A
OCH2CO2H
H
29.1
63.6
O
O
O
OH
15a
15b
A
OCH2CO2H
H
1.4
N
H
10.1
O
O
OH
O
O
16b
A
B
H
13.8
OH
OH
N
H
Br
O
O
17a
17b
OCH2CO2H
H
>250
235
N
Ph
O
O
O
18a
18b
A
A
OCH2CO2H
H
17.7
51.8
OH
F F
19a
19b
OCH2CO2H
H
27.6
60.3
OH
OH
O
20a
20b
Ac
OCH2CO2H
H
22.4
>250
OH
F
F
21a
21b
A
OCH2CO2H
H
77.9
52.1
OH
OH
O
Br
O
O
F
F
22a
22b
A
OCH2CO2H
H
>250
237
O
O
O
23a
24a
B
OCH2CO2H
OCH2CO2H
74.2
153
OH
O
OH
O
Bd
OH

C. P. Holmes et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2719–2724
2723
Table 1 (continued)
Compound
pTyr mimetics
Synthesis method
X
IC50 (lM)
25a
25b
A
OCH2CO2H
H
>250
38
OH
O
O
a PTP1B binding assays were conducted as previously reported in Ref. 12. Values are means of duplicate experiments, errors are usually within 10%.
b Oxidized from 11a and 11b by MCPBA.
c Mixture of two isomers.
d Formed as byproduct during the synthesis of 23a.
and 11b are double those of 3a and 3b), presumably
because sulfur is a weaker hydrogen binding acceptor
compared to an oxygen atom. Further oxidation of
sulfur to sulfoxide (12a and 12b) or sulfone (13a
and 13b) resulted in the loss of the activity, indicat-
ing unfavorable interactions from the sulfoxide or
sulfone. It is also worthwhile to note that 14a and
14b with the 2-benzofurancarboxylic acid group exhi-
bit similar activity as 3a and 3b, indicating that con-
formational constraint of the acid offers little
advantage.
Four pTyr mimetics, difluoroacetic acids 18a and 18b, a-
keto acids 19a and 19b, a-hydroxy acid groups 20a and
20b, and propionic acid 24a, were made with one atom
spacing shorter acidic group compared to 3a and 3a,
and most closely mimic the spacing found in the parent
DFMP group of 1a and 1b. In the oxoacetic acid Series
I, these substitutions resulted in better inhibitors (18a,
19a, and 20a) than 3a, but incorporation in Series II
led to compounds with similar or poorer activity (18b,
19b, and 20b worse than 3b). It has been shown previ-
ously that simple biphenyl or naphthalenyl difluoro-car-
X
O
S
O
NH
X
Method A
a
X
S
b, c
S
O
N
S
N
O
N
O
O
X
d
R
e, c
Cl
Method B
S
N
N
O
S
O
N
H
R
Scheme 1. Methods A and B for preparing triaryl sulfonamides. Reagents and conditions: (a) thiadiazolyl-C6H4-CH2NH2, A-ring sulfonylchloride,
CH2Cl2, DIEA; (b) BrCH2-C-ring pTyr mimetic, K2CO3, CH3CN, 70 °C; (c) CF3CO2H, CH2Cl2 or KOH, MeOH, H2O; (d) H2NCH2-C-ring pTyr
mimetic, DIEA, CH2Cl2; (e) thiadiazolyl-C6H4CH2Br, K2CO3, CH3CN, 70 °C.
X
CHO
Method C
a
HN
O
O
b, c
S
R
N
S
R
R
N
N
S
N
N
Scheme 2. Method C for the synthesis of triaryl sulfonamides. Reagents and conditions: (a) thiadiazolyl-C6H4-CH2NH2, MeOH, Na(OAc)3BH; (b)
XC6H4SO2Cl, DIEA, CH2Cl2; (c) CF3CO2H in CH2Cl2 or KOH, MeOH, H2O.

2724
C. P. Holmes et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2719–2724
boxylates are weak inhibitors of PTP1B,10a while the a-
keto acid and a-hydroxy acid groups had been reported
as pTyr mimitics.17
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18
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afforded compounds 25a and 25b,
which displayed an unusual selectivity relationship be-
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Moody, C. M.; Miguel, J. A.; Ferla, S. W.; De Francisco,
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In conclusion, we have synthesized and evaluated a ser-
ies of triaryl sulfonamide-based PTP1B inhibitors in
which the DFMP group of two lead series has been re-
placed by potential bioisosteric replacements. Although
most of monocharged bioisosteres are not as active as
those dianionic pTyr mimetics, O-bromophenoxyacetic
acid appears to compare favorably with dianionic o-car-
boxymethyl salicylic acid and 2-(oxalyamino)-benzoic
acid. Several mono- or di-charged compounds (8a, 8b,
and 15a) were shown to inhibit PTP1B in the low micro-
molar range, demonstrating the feasibility of using this
systematic approach in identifying non-phosphonate
pTyr mimetics in a small molecular scaffold. The next
step in the optimization of these compounds will be to
address their ability to cross a cell wall to where PTP1B
resides. In addition, the results from this study might
provide an indication of the relative effectiveness of
these pTyr mimetics that would be useful in the further
design and development of PTP1B and perhaps other19
protein–tyrosine phosphatase inhibitors.
12. Li, X.; Bhandari, A.; Holmes, C. P.; Szardenings, A. K.
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