Isothiazolidinone inhibitors of PTP1B containing imidazoles and imidazolines

Article abstract of DOI:10.1016/j.bmcl.2007.11.012

The structure-based design and synthesis of isothiazolidinone (IZD) inhibitors of PTP1B containing imidazoles and imidazolines and their modification to interact with the B site of PTP1B are described here. The X-ray crystal structures of 3I and 4I comple

Full text of DOI:10.1016/j.bmcl.2007.11.012

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 66–71
Isothiazolidinone inhibitors of PTP1B containing
imidazoles and imidazolines
Brent Douty,a,* Brian Wayland,a Paul J. Ala,b Michael J. Bower,a James Pruitt,a
Lori Bostrom,a Min Wei,b Ronald Klabe,b Lucie Gonneville,b Richard Wynn,b
Timothy C. Burn,b Phillip C. C. Liu,b Andrew P. Combsa and Eddy W. Yuea
aIncyte Corporation, Discovery Chemistry, Experimental Station, Route 141 and Henry Clay Road, Wilmington, DE 19880, USA
bApplied Technology, Incyte Corporation, Experimental Station, Route 141 and Henry Clay Road, Wilmington, DE 19880, USA
Received 23 August 2007; revised 31 October 2007; accepted 6 November 2007
Available online 9 November 2007
Abstract—The structure-based design and synthesis of isothiazolidinone (IZD) inhibitors of PTP1B containing imidazoles and imi-
dazolines and their modification to interact with the B site of PTP1B are described here. The X-ray crystal structures of 3I and 4I
complexed with PTP1B were solved and revealed the inhibitors are interacting extensively with the B site of the enzyme.
Ó 2007 Elsevier Ltd. All rights reserved.
The inhibition of protein tyrosine phosphatase 1B
(PTP1B) has attracted much attention in recent years
due to its potential of treating diabetes and obesity.1–3
PTP1B decreases insulin signaling by dephosphorylating
tyrosine residues present in the insulin receptor (IR).4
Inhibition of PTP1B should therefore increase insulin
sensitivity and responsiveness. The data to support this
were reported by two independent laboratories that
showed PTP1B knock-out mice had lower insulin and
glucose levels along with increased sensitivity to insulin
and resistance to high-fat induced weight gain all with-
out any adverse effects.5,6
cover a novel inhibitor of PTP1B using computer-as-
sisted structure-based designs. Our efforts led to the
identification of the isothiazolidinone (IZD) heterocycle
as a very effective mimic of pTyr.14 We have disclosed
the SAR of heterocycles similar to IZD along with the
development of alternatives to the original peptide scaf-
fold which included the use of benzimidazoles and sul-
fonamides to replace amides.15–17
In an effort to further increase binding affinity and selec-
tivity, ligands that interact with the adjacent binding
sites of PTP1B were examined. We had previously deter-
mined that the IZD heterocycle resides deep within the
catalytic or A site of the enzyme as designed.14,15 The
two additional sites, C and E, are solvent-exposed, shal-
low, and contain few enzymatic residues for productive
binding interactions.18,19 Introduction of substituents
into the D site, a very small pocket that interacts with
small substituents attached to the phenyl ring adjacent
to the IZD, provided only a small increase in potency.18
We report herein inhibitors that explore the B site—a
second, non-catalytic phosphate binding site that is rel-
atively close to the catalytic site and contains several
hydrophobic and hydrophilic residues for potential
binding interactions (Val49, Phe52, Ile219, Met258,
Arg24, and Arg254).18,19 We reasoned that the appro-
priate functionalization of our analogs to reach the B
site should produce more potent inhibitors (Fig. 1).
Functionalization of the benzimidazole moiety of inhib-
itor 2 was unattractive since derivatization at the 4 or 5
The research into discovering small molecule inhibitors
of PTP1B has been focused on finding mimics of phos-
photyrosine (pTyr).7–13 The common theme with these
inhibitors is the highly charged and polar functionalities,
such as phosphonates and carboxylates that are used to
occupy the active site of PTP1B. In view of the existing
inhibitors that were already reported in the literature, we
sought a new pTyr mimetic that would not only be a po-
tent inhibitor of PTP1B, but that would also avoid or
minimize the polarity found in the existing inhibitors.
Toward that end, we embarked on a program to dis-
Keywords: PTP1B; Isothiazolidinone; Phosphotyrosine; Protein tyro-
sine phosphatase.
*
Corresponding author. Tel.: +1 302 498 6900; e-mail: bdouty@
incyte.com
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.11.012

B. Douty et al. / Bioorg. Med. Chem. Lett. 18 (2008) 66–71
67
O
O
Ph
O
O
O
N
BocHN
BocHN
H
N
H
N
NH2
NH2
N
H
N
H
NH2
S
O
a
O
S
O
S
O
O
O
O
S
O
S
O
O
N-tBu
N-tBu
NH
NH
O
O
6
7
O
O
1
2
b
CF3
O
•
O
HCl
H2N
R
N
R
H
N
HN
HN
S
NH2
NH2
H
N
H
N
O
O
c
N
Y
X
S
O
X
S
O
O
S
O
S
O
O
O
O
O
S
O
S
O
N-tBu
N-tBu
O
NH
NH
O
O
Y
9
8
O
O
3
4
d
Figure 1. Progression of IZD containing PTP1B inhibitors.
CF3
CF3
NH
•
HCl
H
N
H
N
CN
S
S
OEt
position of the benzimidazole ring had previously pro-
duced a loss of activity or limited SAR.16–18 Isosteric
replacements for the benzimidazole were modeled and
the imidazoline (3) and imidazole (4) produced good
candidates. Both heterocycles could maintain the critical
hydrogen bonding interactions with Asp48 of PTP1B
through the nitrogen atoms which were found to be nec-
essary for high affinity binding in our earlier work.14–16
In this paper, we describe our design and synthesis of
imidazoles and imidazolines as novel PTP1B inhibitors
that bind extensively in the B site.
O
O
O O
e
O
S
O
O
O
S
N-tBu
N-tBu
O
O
10
11
f
g
CF3
CF3
R
R
•
TFA
HN
HN
H
N
H
N
N
N
S
S
The functionalized imidazoles could be easily prepared
from sulfonamide imidates and substituted amino-
methyl ketones. Alternatively, the functionalized imidaz-
olines could also be prepared from the same imidate
intermediate with substituted diamines and chiral dia-
mines that allow the introduction of stereochemistry at
the stereogenic center. The synthesis of functionalized
imidazoles and imidazolines began with the unsaturated
IZD substituted primary amide 6 reported in our previ-
ous work (Scheme 1).15 Reduction of the unsaturated
IZD afforded the (R/S)-IZD primary amide 7. Removal
of the Boc group (7 ! 8), followed by reaction with (3-
CF3Ph)SO2Cl, provided the sulfonamide 9. The primary
amide was dehydrated with trichloroacetyl chloride to
sulfonamide nitrile 10 which was converted to the imi-
date hydrochloride 11. The imidazoles were prepared
from the condensation of 11 and appropriately substi-
tuted 2-amino-methyl ketones.20 The tert-butyl group
was removed from the IZD in TFA upon microwave irra-
diation. The two-step process afforded the sulfonamide
imidazoles 12 in 7–43% yields. The functionalized imi-
dazolines were also prepared from imidate hydrochloride
11 and substituted diamines. The chiral diamines were
derived from amino acids.21,22 Deprotection of the t-bu-
tyl group provided the sulfonamide imidazolines 13 in
38–86% yields. Sulfonamide imidazolines and imidazoles
were prepared as mixtures of diastereoisomers.
O
O
O O
O
S
O
S
O
O
NH
NH
O
O
12
13
Scheme 1. Synthesis of imidazole and imidazoline analogs. Reagents
and conditions: (a) LiBH4, THF, 0 °C ! 25 °C, 2 h, 76%; (b) 4 M HCl
in dioxane, CH2Cl2, 1.5 h, 98%; (c) ((3-CF3)-Ph)SO2Cl, i-Pr2NEt,
CH2Cl2, 75%; (d) CCl3COCl, i-Pr2NEt, CH2Cl2, ꢀ10 °C ! 0 °C, 5 h,
50%; (e) HCl (gas), CH2Cl2/EtOH (2:1), 1 h, quantitative; (f) i—
aminoketone, KOAc, MeOH, D, 16 h; ii—TFA, 130 °C (microwave),
1 min, 7–43%; (g) i—diamine, EtOH, 0 °C ! 25 °C, 1 h; ii—TFA,
150 °C (microwave), 30 s, 38–86%.
The synthesis of analogs with a methyl group adjacent to
the IZD substituent began with commercially available
methyl 4-bromo-3-methylbenzoate 14 (Scheme 2).
Reduction of 14 followed by silylation provided the pro-
tected benzylic alcohol 16. Lithium halogen exchange of
bromide 16 and quenching with triisopropyl borate affor-
ded boronic acid 17. Suzuki coupling of 17 with the
chloro-IZD 18 using PdCl2(dppf)ÆCH2Cl2 catalyst15 and
removal of the TBDMS group provided unsaturated
IZD-alcohol 19 in modest yield. Reduction of 19 gave
the (R/S)-IZD 20 which was converted to the bromide

68
B. Douty et al. / Bioorg. Med. Chem. Lett. 18 (2008) 66–71
Table 1. Comparison of the primary amide with heterocyclic
replacements
OR
OSit-BuMe2
CO2Me
O
S
O
Cl
a
c
N-tBu
+
H
N
O
Br
Br
B(OH)2
R
F3C
S
O
14
15: R = H
17
18
b
O
16: R = t-BuMe2Si
d
O
S
O
Ph
Ph
NH
N
CN
R
OH
O
O
S
O
S
O
S
h
e
O
O
O
5
N-tBu
N-tBu
N-tBu
Compoundsa
R
PTP1Bb
IC50 (nM)
TCPTPb
IC50 (nM)
O
O
O
23
19
20: R = OH
21: R = OMs
22: R = Br
5A
CONH2
5030
5000
f
g
i
F
HN
N
5B
5C
5D
67
240
700
43
H
N
H2N
CN
CN
S
j
HN
N
O
O
270
500
O
S
O
O
O
S
N-tBu
N-tBu
HN
N
O
O
24
25
a Compounds tested as mixture of diastereoisomers.
b pNPP enzyme assay.
Scheme 2. Synthesis of key intermediate 25. Reagents and conditions:
(a) LAH, Et2O, 0 °C ! 25 °C, 30 min, 90%; (b) t-BuMe2SiCl, imidazole,
DMF, 0 °C ! 25 °C, 1 h (94%); (c) i—n-BuLi, THF, ꢀ78 °C, 30 min;
ii—(i-PrO)3B, ꢀ78 °C ! 25 °C, 99%; (d) i—PdCl2 (dppf)ÆCH2Cl2,
K2CO3, 80 °C, 24 h; ii—TBAF, THF, 0 °C ! 25 °C, 1 h, 39% (two
steps); (e) Li(s-Bu)3BH, THF, ꢀ78 °C, 15 min, 81%; (f) MsCl, Et3N,
CH2Cl2, ꢀ10 °C, 15 min, 96%; (g) NaBr, DMA, 30 min, 98%; (h) i—
Ph2C@NCH2CN, t-BuOK, ꢀ78 °C, 30 min; ii—22, THF,
ꢀ78 °C ! 25 °C, 30 min, 95%; (i) 1 N HCl, THF, 1.5 h, 88%; (j) ((3-
F)-Ph)SO2Cl, pyridine, 1 h, 99%.
to be an effective replacement for the N-terminal peptide
portion of the inhibitor.16 In later work the 3-fluoro
substituted sulfonamide was used and found to produce
inhibitors of similar potency. Substitution of the imidaz-
oline with (R)-methyl (3A) enhanced potency, while (S)-
methyl (3B) decreased activity compared with the
unsubstituted imidazoline 5D. Dimethyl substitution
(3C) also decreased activity. The difference in activity
between the (R)- and (S)-isomers became greater with
phenyl and benzyl substituents (approximately 9-fold).
The (R)-benzyl analog 3F was approximately 5-fold
more potent compared with the unsubstituted imidazo-
line 5D. This indicated additional binding interactions
were being made between the enzyme and the (R)-substi-
tuted imidazoline. To enhance potency further only the
(R)-substituted imidazolines were prepared.
22 via mesylate 21. The imine protected amino-cyano
group was introduced by alkylation of bromide 22 with
N-(diphenylmethylene)-aminoacetonitrile23 to give 23.
The benzophenone imine of 23 was removed (23 ! 24),
and sulfonylation provided sulfonamide nitrile 25. Sul-
fonamide nitrile 25 provided access to all functionalized
imidazoles and imidazolines with the methyl group adja-
cent to the (R/S)-IZD as mixtures of diastereoisomers.
The unsubstituted imidazole 5C and imidazoline 5D
containing inhibitors were 21- and 7-fold more potent
than the primary amide 5A, respectively, but were less
potent than the benzimidazole containing inhibitor 5B
(Table 1). The potency of the imidazole and imidazoline
series was optimized with inhibitors that were able to ac-
cess the B site.
The (R)-(o)-fluorobenzyl analog (3I) was 3-fold more
potent than the corresponding analog without the fluo-
rine substituent (3H). An X-ray crystal structure of 3I
bound to the enzyme was obtained to explore the po-
tency enhancement (Fig. 2). Similar to previously
prepared IZD inhibitors,14–17 the isomer that was ob-
served to be bound to the enzyme was the (S)-IZD iso-
mer and the center adjacent to the sulfonamide had the
(S)-configuration.24 The structure shows the aryl sulfon-
amide p-stacks on top of the imidazoline. One of the sul-
fonamide oxygens forms a hydrogen bond to the
backbone amide of Arg47 through a bridging water
molecule and the imidazoline NH forms a hydrogen
bond to Asp48 of the enzyme. The benzyl substituent
binds in the B site in a similar position as the aryl group
of the phosphotyrosine substrate.25 B site interactions
A small library of substituted imidazoline inhibitors was
prepared and tested for activity in PTP1B (Table 2). The
compounds were also tested for selectivity against T-cell
PTP (TCPTP), which is highly structurally related to
PTP1B. TCPTP is important for normal T-cell activa-
tion and therefore having selectivity for PTP1B is desir-
able.13 Initially, the 3-trifluoromethyl substituted
sulfonamide was used as it was previously determined

B. Douty et al. / Bioorg. Med. Chem. Lett. 18 (2008) 66–71
69
Table 2. Imidazoline PTP1B inhibitors
R
HN
H
N
N
Y
X
S
O
O
O
S
O
NH
O
3
Compoundsa
X
R
Y
PTP1Bb IC50 (nM)
TCPTPb IC50 (nM)
3A
3B
3C
3D
3E
3F
3G
3H
3I
CF3
CF3
CF3
CF3
CF3
CF3
CF3
F
(R)-Me
(S)-Me
H
H
H
H
H
H
H
H
H
H
540
810
930
660
2900
150
1300
210
64
420
670
700
430
2070
120
1100
140
38
Di-Me
(R)-Ph
(S)-Ph
(R)-CH2Ph
(S)-CH2Ph
(R)-CH2Ph
F
(R)-CH2(2-F-Ph)
(R)-(CH2)2Ph
(R)-CH2O(3-SO2Me-Ph)
3J
F
130
800
23
68
3K
3L
3M
3N
3O
F
Me
Me
Me
Me
Me
470
25
F
(R)-(CH2)2O(3-SO2Me-Ph)
(R)-(CH2)3O(3-SO2Me-Ph)
F
160
110
22
84
65
F
(R)-(CH2)4O(2-CO2Me,3-OH-Ph)
(R)-(CH2)4O(2-CO2H,3-OH-Ph)
F
46
a Compounds tested as mixture of diastereoisomers.
b pNPP enzyme assay.
An X-ray crystal structure of the phenethyl substituted
imidazoline (3J)24,26 bound to PTP1B also shows the
aromatic ring binding in the B site just above Ile219
and Met258. The slight loss in potency compared with
3I (2-fold) is explained by a loss of the interactions be-
tween the fluorine substituent and the enzyme that are
present in compound 3I.
To reach further into the B site, the chain length to the aryl
substituent was increased. Polar functionalities on the
aryl group were placed at the end of the chain in an at-
tempt to interact with the polar residues in the B site. Sul-
fonates and salicylates were used to obtain additional
binding interactions with the B site. The (o)-methyl substi-
tuent on the aromatic ring adjacent to the IZD substitu-
ent, that previously was found to enhance potency
through D site interactions, was also incorporated.
In the sulfonate analogs the addition of one methylene
in the chain greatly enhanced potency (approximately
35-fold, 3L vs 3K). Extending the chain further resulted
in a loss of activity. The salicylate analogs were also po-
tent inhibitors. The salicylic acid analog (3O) was 5-fold
more potent than the methyl salicylate analog 3N, and
was approximately 2-fold more active against PTP1B
versus TCPTP. It was also 32-fold more active than
the unsubstituted imidazoline 5D and the most active
in the series.
Figure 2. X-ray crystal structure of 3I bound to PTP1B. PDB
deposition number 2VEW.
produced the approximately 5-fold increase in potency
compared with the unsubstituted imidazoline 5D. The
3-fold increase in potency due to the fluorine substituent
(3I vs 3H) was also apparent from the X-ray structure
which shows the fluorine substituent in close proximity
with Val49, Ile219, and Gln262 of the enzyme in a
hydrophobic pocket of the B site.
Next a small library of substituted imidazole inhibitors
was prepared. As with the imidazoline series, the 3-trifluo-
romethyl and 3-fluoro substituted sulfonamides

70
B. Douty et al. / Bioorg. Med. Chem. Lett. 18 (2008) 66–71
Table 3. Imidazole PTP1B inhibitors
R
HN
H
N
N
Y
X
S
O
O
O
S
O
NH
O
4
Compoundsa
X
R
Y
PTP1Bb IC50 (nM)
TCPTPb IC50 (nM)
4A
4B
4C
4D
4E
4F
4G
4H
4I
CF3
CF3
CF3
CF3
CF3
F
Ph
CH2Ph
CH2CH2Ph
H
100
300
170
52
61
230
170
51
H
H
CH2CH2CH2Ph
CH2CH2CH2CH2Ph
Ph
H
H
200
160
250
180
43
160
90
H
F
CH2Ph
CH2CH2Ph
H
270
100
24
F
H
F
CH2CH2CH2Ph
CH2CH2CH2CH2Ph
H
4J
F
H
260
350
120
160
32
110
170
170
170
46
4K
4L
4M
4N
F
(CH2)3O(2-CO2Me,3-OH-Ph)
(CH2)3O(2-CO2H,3-OH-Ph)
(CH2)4O(2-CO2Me,3-OH-Ph)
(CH2)4O(2-CO2H,3-OH-Ph)
Me
Me
Me
Me
F
F
F
a Compounds tested as mixture of diastereoisomers.
b pNPP enzyme assay.
produced inhibitors of similar potency (Table 3). Substi-
tution of the imidazole ring with phenyl (4A) increased
potency approximately 2-fold compared with the unsub-
stituted imidazole (5C). X-ray crystal structures of the
phenyl and benzyl analogs (4A and 4B) with PTP1B
showed that the phenyl group of both analogs interacted
with Phe182 of the enzyme, but indicated longer chain
lengths would be necessary to reach the B site.24,26
As the chain length was increased, the activity of the
analogs remained similar until the chain length between
the imidazole and phenyl substituent reached three
methylenes. At that point the optimum chain length of
the phenyl analogs was reached (4D and 4I). Compound
4I was approximately 5-fold more active than the unsub-
stituted imidazole 5C. The addition of one methylene in
the chain (4E and 4J) reduced potency compared with
the optimum 3-carbon chain length. The potency
decreased to that of the unsubstituted imidazole 5C.
An X-ray crystal structure of compound 4I24 bound to
PTP1B (Fig. 3) showed the phenyl group was binding
in the B site directly above Ile219, Met258, and
Gln262. The sulfonamide oxygens and imidazole nitro-
gens formed hydrogen bonds with the enzyme in a sim-
ilar manner as imidazoline analog 3I.
Figure 3. X-ray crystal structure of 4I bound to PTP1B. PDB
deposition number 2VEY.
methyl salicylate analogs, the addition of one methylene
in the chain enhanced potency 2-fold (4K vs 4M). The
same pattern was observed with the salicylic acid ana-
logs (4L vs 4N). As with the imidazoline series, salicylic
acid analog 4N was 5-fold more potent than the methyl
salicylate analog 4M, and was the most active in the
imidazole series. Compound 4N was now approximately
7-fold more active than the unsubstituted imidazole 5C.
The (o)-methyl substituent on the aromatic ring adjacent
to the IZD substituent was again incorporated to obtain
D site interactions and to maximize potency. We also
incorporated the salicylate substituent that produced
the highest activity in the imidazoline series. With the

B. Douty et al. / Bioorg. Med. Chem. Lett. 18 (2008) 66–71
71
8. Blaskovich, M. A.; Kim, H.-O. Expert Opin. Ther. Pat.
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2725.
Polar B site substituents (sulfonates and salicylates) pro-
duced the most potent inhibitors with both the imidazo-
line (3L and 3O) and the imidazole (4N) scaffolds.
Previously the salicylate substituent of our peptidic
IZD analog was shown to bind in the B site.18 The salic-
ylate formed hydrogen bonds with Arg24 and Arg254 of
the enzyme’s B site. Presumably the sulfonate and salic-
ylate containing inhibitors reported here are interacting
with B site Arg residues in a similar manner. Salicylate
containing inhibitors have previously been reported to
produce 20-fold selectivity for PTP1B over TCPTP.27
We observed only minimal specificity (2-fold) with salic-
ylate analog 3O in the imidazoline series. The same spec-
ificity was not observed in the imidazole series or other
imidazoline analogs.
13. Bialy, L.; Waldmann, H. Angew. Chem. Int. Ed. Engl.
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Sparks, R.; Glass, B.; Modi, D.; McLaughlin, E.;
Bostrom, L.; Li, M.; Galya, L.; Blom, K.; Hillman, M.;
Gonneville, L.; Reid, B. G.; Wei, M.; Becker-Pasha, M.;
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McLaughlin, E.; Takvorian, A.; Wasserman, Z.; Bower,
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Rupar, M.; Ala, P. J.; Reid, B. G.; Ellis, D.; Gonneville,
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The imidazoline and imidazole were discovered as viable
replacements for the benzimidazole. While initially the
affinity of the unsubstituted imidazoline (5D) and imid-
azole (5C) decreased compared to the benzimidazole
(5D), functionalization to interact with the B site pro-
duced two highly potent PTP1B inhibitors 3O and 4N.
B site interactions increased the affinity 32-fold (3O vs
5D) in the imidazoline series and 7-fold (4N vs 5C) in
the imidazole series. X-ray crystal structures of the imi-
dazolines and imidazoles bound to PTP1B showed the
phenyl substituent on the end of the methylene chain
optimally interacting with the hydrophobic residues of
the B site when the chain length was sufficiently long en-
ough to extend deep into the B site.
Acknowledgments
18. Ala, P. J.; Gonneville, L.; Hillman, M. C.; Becker-Pasha,
M.; Wei, M.; Reid, B. G.; Klabe, R.; Yue, E. W.;
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Bower, M.; Combs, A. P.; Burn, T. C.; Hollis, G. F.;
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We thank Laurine Galya, Mei Li, James Doughty, and
Karl Blom for NMR spectroscopic, analytical, and mass
spectroscopic assistance.
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Supplementary data
X-ray crystal structures of 3J, 4A, and 4B complexed
with PTP1B can be found, in the online version, at
doi:10.1016/j.bmcl.2007.11.012.
20. Liu, J.; Ikemoto, N.; Petrillo, D.; Amrstrong, J. D.
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