Discovery of novel and potent heterocyclic carboxylic acid derivatives as protein tyrosine phosphatase 1B inhibitors

Article abstract of DOI:10.1016/j.bmcl.2012.02.070

A series of novel heterocyclic carboxylic acid based protein tyrosine phosphatase 1B (PTP1B) inhibitors with hydrophobic tail have been synthesized and characterized. Structure-activity relationship (SAR) optimization resulted in identification of several

Full text of DOI:10.1016/j.bmcl.2012.02.070

Bioorganic & Medicinal Chemistry Letters 22 (2012) 2843–2849
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of novel and potent heterocyclic carboxylic acid derivatives
as protein tyrosine phosphatase 1B inhibitors
Sujay Basu a,b, , Uppuleti Viplava Prasad b, Dinesh A. Barawkar a, Siddhartha De a, Venkata P. Palle a,
⇑
Suraj Menon a, Meena Patel a, Sachin Thorat a, Umesh P. Singh a, Koushik Das Sarma a, Yogesh Waman a,
Sanjay Niranjan a, Vishal Pathade a, Ashwani Gaur a, Satyanarayana Reddy a, Shariq Ansari a
a Drug Discovery Facility, Advinus Therapeutics Ltd, Quantum Towers, Plot-9, Phase-I, MIDC, Hinjewadi, Pune 411057, India
b Department of Organic Chemistry, Andhra University, Visakhapatnam 530003, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel heterocyclic carboxylic acid based protein tyrosine phosphatase 1B (PTP1B) inhibitors
with hydrophobic tail have been synthesized and characterized. Structure–activity relationship (SAR)
optimization resulted in identification of several potent, selective (over the highly homologous T-cell pro-
tein tyrosine phosphatase, TCPTP) and metabolically stable PTP1B inhibitors. Compounds 7a, 19a and 19c
showed favorable cell permeability and pharmacokinetic properties in mouse with moderate to very
good oral (% F = 13–70) bio-availability.
Received 30 September 2011
Revised 10 February 2012
Accepted 23 February 2012
Available online 1 March 2012
Keywords:
Protein tyrosine phosphatase 1B
Diabetes
Ó 2012 Elsevier Ltd. All rights reserved.
Carboxylic acid
Heterocycle
Metabolic stability
Type 2 diabetes (T2D) and obesity have emerged as major health
care burden around the world. Insulin resistance has been estab-
lished as a key defect in progression to and maintenance of T2D.
Major current pharmacotherapies for T2D include sulfonylureas,
glucose on a high fat diet.7 This unique combination of desired
attributes has driven an intense search for PTP1B inhibitors for
treatment of both, T2D and obesity. Reduced PTP1B levels by the
use of specific antisense oligonucleotide (ISIS-113715, Phase 2, dis-
continued) in db/db and ob/ob mouse further reinforce the poten-
tial of this target.8 Over the past several years, a considerable
amount of efforts has been put in discovering PTP1B inhibitors for
beneficial effect in T2D and obesity patients.9 Most of the small
PTP1B inhibitors bear highly charged phosphonates10 or multiple
acid and peptide functionalities.11 These inhibitors show poor cell
permeability and oral bioavailability due to presence of negatively
charged polar residues. Our goal was to discover novel, potent, cell
permeable and orally bio-available PTP1B inhibitors by designing
low molecular weight, non-phosphonate and mono carboxylic acid
phosphotyrosyl (pTyr) mimetics inhibitors based on known litera-
ture compounds I and II (Fig. 1). Recently heterocyclic carboxylic
acid derivatives have been reported as a new pTyr surrogate.12
The oral bio-availability of compound I in rats is only 13% and
demonstrated in vivo efficacy.10a The compound II shows moderate
cellular permeability (Papp > 1 ꢀ 10ꢁ6 cm/s) in a Caco-2 cell mem-
metformin, thiazolidinediones (PPAR
c
agonist1), gliptins (DPPIV
inhibitors) and liragutide (GLP-1 agonist). These pharmacothera-
pies have their own limitations with respect to their efficacy or side
effects like nausea, diarrhea, hypoglycemia, weight gain, fluid
retention and cardiovascular complications.2 This makes discovery
of new and safe treatments essential for T2D. PTP1B plays an impor-
tant role in insulin receptor signaling.3 PTP1B is an intracellular
protein tyrosine phosphatase expressed in insulin responsive
tissues including the classical insulin targeted tissues such as liver,
muscle and fat.4 PTP1B dephosphorylates the insulin receptor dur-
ing its biosynthesis in endoplasmic reticulum as well as after it has
been stimulated by the insulin and thus play a central role in neg-
ative regulation of insulin signaling pathway.5 Recent evidence sug-
gest that PTP1B is also involved in negative regulation of leptin
signaling by inhibiting phosphorylation of JAK2, which attenuates
leptin signaling in vivo.6 Studies from two independent groups have
shown that mice that lack the PTP1B gene have improved insulin
sensitivity with resistance to weight gain and reduced plasma
brane assay and good selectivity over the TCPTP (Ki = 164 l
M).13
Structural hybridization of compound I and II was carried out with
the view that (i) to lower the negative charge of compound I by
replacing difluoromethylene phosphonate (DFMP) head group by
isoxazole carboxylic acid employed in II, as shown in 7a, (ii) by
replacing flexible extended methyleneoxy linker of compound II
⇑
Corresponding author. Tel.: +91 20 66539600; fax: +91 20 66539620.
E-mail address: sujay.basu@advinus.com (S. Basu).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2012.02.070

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S. Basu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2843–2849
Br
O
OH
OH
P
F
O
F
O
I
Merck Frosst
IC50(PTP1B): 120 nM
O
O
Hybridization
Optimization
O
O
N
O
N
OH
OH
N
O
N
O
OH
F
N
7a
19c
O
Cl
O
OH
O
O
II
Abbott
Ki(PTP1B): 6.9 µM
Figure 1. Structure of PTP1B inhibitors.
Figure 2. The docked pose of compound 19a (bright orange) overlayed (A) with co-crystal structure of compound I (light blue) from pdb id 3CWE, (B) with co-crystal
structure of compound II (light pink) from pdb id 1XBO and (C) with docked posed of 19c (magenta). The protein structure from pdb id 3CWE was used for docking and is
shown in green. The oxygen (O), nitrogen (N) and chlorine (Cl) atoms are colored in red, blue and green respectively. Docking was done using program GOLD. The docked
poses of compounds were further minimized using program MOE. The putative hydrogen bonds are shown by dotted line. The atomic numbering used here is from pdb id
1XBO.
with rigid oxadiazole linker as shown 19a in order to make mole-
cule rigid and thus more preorganized for binding to PTP1B. Herein
we report a series of heterocyclic carboxylic acid derivatives as
PTP1B inhibitors that led to discovery of compound 19c with
improved pharmacokinetic profile.
Molecular modeling was used to understand the binding mode
of proposed compounds. Figure 2 shows compound 19a docked
into active site of PTP1B (pdb id 3CWE) along with ligands from
pdb id 3CWE and pdb id 1XBO (Fig. 2A and B, respectively). The
model exhibited that the isoxazole carboxylic acid of 19a used to
replace DFMP head group of compound I provided the desired
complementarity for recognition by active site by providing hydro-
gen bond acceptor for backbone amide nitrogen of Ser216 and io-
nic interaction for side chain of Arg221 (Fig. 2A), similar to the
carboxylic acid of compound II observed in crystal structure of
Initial SAR efforts were focused on the optimization of heterocy-
cles containing carboxylic acid moiety as a head group, that
involved replacement of DFMP group of I and retaining 1,2-diphe-
nyl ethanone linker. The synthesis of target compounds 7a–h (Table
1) involved typical synthesis of key benzyl bromide intermediates
4a–h (Scheme 1) and is outlined in Scheme 2. The starting materials
1a–e, 1g–h and 2 were prepared by literature procedures.14 Com-
pound 2 was treated with 4-(hydroxymethyl)phenylboronic acid
under Suzuki condition15 to obtain benzyl alcohol derivative 3
which was converted to corresponding key benzyl bromide 4f using
PBr3. Compound 1a–e and 1g–h were converted to corresponding
key benzyl bromide intermediates (4a–e, 4g–h) using N-bro-
mosuccinimde (NBS) in refluxing benzene. Benzyl bromide (4a–h)
derivative thus synthesized was treated with commercially avail-
able 1,2-diphenyl ethanone (5) using sodium hydride (NaH) as base
in N,N-dimethylformamide (DMF) at temperature 10–15 °C to
obtain 6a–h (Scheme 2) which upon hydrolysis with (1 N) NaOH
at room temperature provided target compound 7a–h in overall
good yields.
1XBO (Fig. 2B). The central phenyl ring shows p–p interaction with
Tyr46. Replacement of flexible and extended methyleneoxy linker
by rigid oxadiazole bearing terminal phenyl group in 19a brings
additional recognition element of
p–p interaction with Phe182
(Fig. 2A and B) this particular interaction was not possible either
with I or II. Compound 19c (Fig. 2C) may be showing better activity
due to extra putative hydrogen bonding interaction between it’s
methoxy group of terminal phenyl and Arg47 of PTP1B as well as
increased hydrophobic interaction between inhibitors –Cl atom
with the nearby hydrophobic pocket of the protein (Fig 2C).
To further examine role of various substitutions on both the
phenyl rings of 1,2-diphenyl ethanone linker with isoxazole and
thiazole carboxylic acid as head group, target compounds 12a–d
and 14c–d (Table 1) were synthesized as illustrated in Scheme 3.
Commercially available phenyl acetic acid derivatives 8a–d
were converted to corresponding Weinreb amides 9a–d using

S. Basu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2843–2849
2845
Table 1
N,O-dimethylhydroxylamine hydrochloride in presence of 1,10-car-
bonyldiimidazole (CDI) and triethylamine (Et3N) in dichlorometh-
ane (DCM) at room temperature. These amides 9a–d were then
treated with an appropriate Grignard reagent in diethyl ether at
temperature 0–15 °C to obtain corresponding 1,2-diphenyl etha-
none derivatives 10a–d in overall good yield. The compounds
10a–d were treated with compound 4a and 10c–d with 4e using
NaH as base in DMF at temperature 10–15 °C to obtain 11a–d
and 13c–d, respectively. Compounds 11a–d and 13c–d upon
hydrolysis with (1 N) NaOH at room temperature provided target
compounds 12a–d and 14c–d (Table 1).
Synthesis of target compounds 19a–c, 21b and 21d, replacing
flexible and extended linker of II by rigid oxadiazole is described
in Scheme 4. Commercially available benzonitrile 15a–d were trea-
ted with aqueous hydroxylamine hydrochloride in ethanol at re-
flux temperature to obtain corresponding hydroxyl benzamidine
derivatives 16a–d which were further treated with commercially
available phenyl acetic acid derivatives in presence of CDI in
DMF at temperature 70–75 °C to provide oxadiazole derivatives
17a–d. These oxadiazole derivatives (17a–d) were condensed
either with 4a or 4e using NaH as base in DMF at temperature
10–15 °C followed by ester hydrolysis with (1 N) NaOH to give
19a–c or 21b and 21d, respectively in overall good yields.
Optimization of heterocycle and 1,2-diphenyl ethanone analogs as PTP1B inhibitors
R2
R3
R4
R5
1
O
R
R6
Compd
R2
H
R3
H
R4
R5
R6
R1
Ki (lM)
OH
7a
H
H
H
H
H
H
N
1.1
O
O
OH
N
N
7b
7c
H
H
H
H
16.3
7.8
N
O
H
N
N
OH
H
H
H
H
H
H
O
O
OH
7d
7e
H
H
H
H
7.8
1.2
The synthesized compounds were assayed in a fluorescence-
based kinetic assay using p-nitrophenyl phosphate (pNPP) as the
substrate with recombinant human PTP1B enzyme. The inhibitory
potency of the compounds was expressed as inhibitory constant
(Ki). Our initial SAR was focused on the replacement of highly neg-
atively charged DFMP head group of I carrying two negative
charges by various heterocycles carrying less negatively charged
group such as carboxylic acid moiety as utilized in II and the re-
sults are summarized in Table 1. Isoxazole containing carboxylic
O
O
OH
N
S
H
H
H
OH
O
7f
H
H
H
H
H
H
H
H
H
H
2.9
7.7
N
O
acid (7a, Ki: 1.1 lM) was found to be more potent than II (Fig. 1)
OH
7g
suggesting more rigid linker is preferred over flexible linker. When
other heterocycles like pyrazole, oxazole, thiazole, pyrrole, pyrrol-
idone were explored for improving potency, only thiazole (7e, Ki:
O
N
O
OH
1.2 lM) and pyrrole (7f, Ki: 2.9 lM) showed improved potency as
7h
7i
H
H
H
H
H
H
H
H
H
H
5.1
compared to II and comparable to compound 7a. As the active site
of PTP1B is highly cationic, we tried to increase the negative-
charge density by introducing a second carboxylic acid moiety on
O
N
HO
O
OH
isoxazole ring (7i, Ki: 40 lM) of 7a (prepared similar to 7a as
40
shown in Scheme 1 and 2) and resulted into 40-fold loss of po-
tency. This could be either due to steric factors or charge–charge
repulsion due to presence of a negatively charged residue Asp181
close to second substituted carboxylic group in 7i. Compound 7a
and 7e were found to be metabolically stable in both mouse and
rat liver microsomes as well as good permeability in parallel artifi-
cial membrane permeation assay (PAMPA)16 (Table 3) and thus
were taken for further optimization of the series. To explore SAR,
different substituents on both phenyl ring of hydrophobic tail part
of 7a and 7e were introduced. Compounds 12a–c and 14c are
found to posses improved potency than compound II and were
equipotent to compound 7a and 7e in PTP1B enzyme assay. Chloro
containing compound 12d (Ki: 0.8 lM) and 14d (Ki: 0.6 lM)
showed slightly improved inhibitory activity in PTP1B enzyme
assay.
As above SAR results demonstrate that the isoxazole and thia-
zole containing carboxylic acid head group contributes signifi-
cantly to the in vitro potency, these head groups were kept fixed
to optimize the replacement of flexible linker of II and results are
summarized in Table 2.
Replacing keto group of 1,2-diphenyl ethanone with more rigid
oxadiazole in compound 7a yielded compound 19a (Ki: 4.0 lM)
N
O
O
O
O
O
OH
O
12a
12b
12c
12d
H
H
H
F
F
F
F
F
F
H
F
F
N
N
N
N
2.4
1.5
1.4
0.8
OH
O
H
F
H
H
H
OH
O
F
OH
H
Cl
O
N
O
O
OH
14c
14d
H
F
F
F
F
F
H
H
1.8
0.6
S
O
OH
N
H
Cl
which is equipotent to compound II. Attempt was made to improve
potency by introducing different substituents on tail phenyl ring in
S

2846
S. Basu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2843–2849
O
R
R
O
i
iii
ii
N
H
O
Br
N
BOC
2
Br
HO
O
1a-e
1g-h
4a-h
3
a
b
c
d
e
O
f
g
h
O
O
O
O
O
O
O
O
O
O
O
O
R=
N
N
N
N
N
N
O
N
N
O
O
N
O
N
O
O
H
BOC
S
O
Scheme 1. Reagents and conditions: (i) NBS, AIBN, benzene, 80 °C, 24 h; (ii) 4-(hydroxymethyl)phenylboronic acid, Na2CO3, Pd(PPh3)4, DMF, water, 110 °C, 16 h; (iii) PBr3,
DCM, 0–5 °C, 3 h.
i
ii
+
4a-h
7c
1
R
O
R
O
7a-h
7f
O
6a-h
5
7a
7b
7d
7e
7g
7h
O
O
O
O
OH
OH
OH
OH
1
OH
OH
OH
R
=
OH
N
N
N
N
N
N
H
N
H
O
N
O
O
O
O
N
O
N
O
S
O
Scheme 2. Reagents and conditions: (i) NaH, DMF, 10–15 °C, 3 h; (ii) 1 (N) NaOH, THF/MeOH (3:2), 25 °C, 12 h.
R2
R4
R5
MgBr
ii
R3
R2
R3
N
R2
R3
OH
R6
,
i
O
R4
R5
O
O
O
R6
8a-d
9a-d
10a-d
R2
R2
R3
R3
4a, iii
iv
10a-d
R4
R5
R4
R5
O
O
O
O
N
N
O
O
O
OH
R6
R2
R6
11a-d
12a-d
R2
R3
R3
4e, iii
iv
10c-d
R4
R5
R4
R5
S
S
O
O
N
N
R6
R6
O
O
O
HO
14c-d
13c-d
Scheme 3. Reagents and conditions: (i) CDI, N,O-dimethylhydroxylamine, HCl, Et3N, DCM, 25 °C, 6 h; (ii) Et2O, 0–5 °C, 4 h; (iii) NaH, DMF, 10–15 °C, 3 h; (iv) 1 (N) NaOH, THF/
MeOH (3:2), 25 °C, 12 h.

S. Basu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2843–2849
2847
R9
OH
OH
N
R7
R8
9
O
R7
R8
R
, ii
N
i
NH2
N
O
N
R7
15a-d
16a-d
17a-d
R8
R9
R9
O
O
O
N
O
N
N
O
N
iv
4a, iii
4e, iii
N
N
O
O
OH
R7
R7
R9
18a-c
19a-c
R8
R9
R8
17a-d
iv
S
S
N
O
N
O
N
N
N
N
O
OH
R7
R7
O
O
R8
20b, 20d
R8
21b, 21d
Scheme 4. Reagents and conditions: (i) aq NH2OH, EtOH, 70–75 °C, 8 h; (ii) CDI, DMF, 80 °C, 20 h; (iii) ButOK, THF, 5–10 °C, 2 h; (iv) 1 (N) NaOH, THF/MeOH (3:2), 25 °C, 12 h.
Table 2
Table 3
Oxadiazole analogs as PTP1B inhibitors
In vitro DMPK
R9
Compd
PAMPA (Papp ꢀ 10ꢁ6 cm/s)
MRa (nmol/min/mg)
MLM
RLM
7a
7e
103
85
8
16
168
45
4
48
10
6
0.06
0.05
0.01
0.00
0.00
0.04
0.00
0.00
0.00
0.00
0.02
0.02
0.02
0.01
0.00
0.03
0.01
0.03
0.01
0.04
1
O
N
N
R
12b
12c
12d
19a
19b
19c
21b
21d
R7
R8
Compd
R7
H
R8
H
R9
H
R1
Ki (lM)
OH
a
19a
4.0
N
Metabolic Rate (MR) <0.1 nmol/min/mg or 80% remaining at 30 min is consid-
ered as metabolically stable. MLM, Mouse liver microsomes; RLM, Rat liver
microsomes
O
O
O
OH
19b
19c
H
H
OMe
Cl
F
0.4
0.3
N
N
O
Selectivity with closest homologue of PTP1B particularly TCPTP
is essential as its inhibition is lethal. Hence, in vitro selectivity of
selected compounds from ethanone derivatives (7a, 12d and
14d) and oxadiazole derivatives (19a–c) were examined against
TCPTP using pNPP assay, and found to be selective (<10% inhibition
OH
OMe
F
O
N
O
O
OH
OH
21b
21d
F
F
H
H
0.5
0.5
at 100 lM) over TCPTP (data not shown).
Having identified compounds with acceptable potency in PTP1B
enzyme assay, we decided to further investigate metabolic stability
and permeability of these compounds; results are summarized in
Table 3. Compounds from ethanone derivatives (7a, 7e, and 12b–
d) and oxadiazole derivatives (19a–c, 21b, 21d) were found to be
metabolically stable in both mouse and rat liver microsomes. The
simple unsubstitued ethanone and oxadiazole derivatives as in
7a, 7e and 19a, as well as substituted ethanone in 12d and oxadi-
azole in 19c showed good permeability in PAMPA. The other
substituted compounds from ethanone derivatives (12b–c) and
oxadiazole derivatives (19b, 21b and 21d) show a substantially re-
duced permeability in PAMPA.
S
O
OMe
N
S
compound 19a. Small hydrophobic substitutions like –Cl, –F and
hydrophilic substitution like –OMe (examples 19b–c, 21b and
21d) significantly improved inhibitor activity as compared to com-
pound II. The SAR revealed that both isoxazole and thiazole ana-
logs were comparable in terms of potency.

2848
S. Basu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2843–2849
3.0
2.5
2.0
1.5
1.0
0.5
0.0
(A)
(B)
150
125
100
75
50
25
0
0
5
10
[I] µM
15
20
0
2
4
6
8
10 12 14 16 18 20 22
[I] µM
Figure 3. Inhibition of compound 19c on the hydrolysis of pNPP by PTP1B suggesting that 19c is a non competitive inhibitor.
encouragement. Analytical and CCO departments are being
acknowledged for their help during this work. We thank Dr. Anup
Ranade for managing intellectual property. Advinus publication no.
ADV-A-016.
Table 4
Pharmacokinetic profilea of compounds 12d, 19a and 19c in male C57BL/6J mice
Compd
12d
19a
19c
Route of administration
Dose (mg/kg)
iv
po
iv
po
iv
po
3
30
3
30
3
30
Cmax
Tmax (h)
AUC0–t
Vss (L/Kg)
CL (mL/min/Kg)
t1/2(h)
(
l
M)
4.5
0.083
2.4
4
38
1.9
NA
1.9
1.0
3.0
NA
NA
NA
13
1.5
0.08
1.8
4.8
63
7.2
1.0
13
NA
NA
NA
70
1.87
0.083
0.98
4.00
99.0
1.08
NA
1.34
1.0
3.60
NA
NA
NA
36
Supplementary data
(l
M h)
Supplementary data (PTP1B, TCPTP, metabolic stability, kinetic
study screening assay protocol; in vivo pharmacokinetics; spectral
characterization of key compounds) associated with this article can
be found, in the online version, at doi:10.1016/j.bmcl.2012.02.070.
1.0
NA
F (%)
a
Values indicate mean for n = 3. iv formulation: N-methyl-2-pyrrolidinone (10%),
References and notes
PEG300 (15%), 0.1 M ammonium acetate buffer qs; po (oral) formulation: Tween 80
(1%), 0.5% w/v NaCMC qs; NA: not applicable.
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To understand the inhibitory modality of this class of com-
pounds, the most potent inhibitor 19c was selected for enzymatic
kinetic analysis on PTP1B using pNPP as substrate. The effect of
compound 19c on PTP1B catalyzed reaction was studied at three
different concentrations (Fig. 3). The data suggests that compound
19c is a non-competitive inhibitor as the Km value retained invari-
able while Vmax value decreases with increasing compound
concentration.
As compounds 12d, 19a and 19c showed good metabolic stabil-
ity and intrinsic permeability, we further evaluated them in mouse
pharmacokinetic study and the results are summarized in Table 4.
Compound 12d displayed moderate plasma clearance (ꢂ50% of he-
patic blood flow) with elimination half-life of 2 h with marginal oral
bio-availability (% F = 13). Compound 19a exhibited excellent oral
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In summary, we have identified potent heterocyclic carboxylic
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Acknowledgments
Authors are grateful to Drs. Rashmi Barbhaiya, Kasim A.
Mookhtiar and Narayanan Hariharan for their support and

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