Bioorganic & Medicinal Chemistry Letters
Synthesis and biological evaluation of novel bis-aromatic amides
as novel PTP1B inhibitors
Wen-Long Wang a,b, , , Chao Huang a, , Li-Xin Gao b, , Chun-Lan Tang b, Jun-Qing Wang a, Min-Chen Wu a,
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Li Sheng b, Hai-Jun Chen b, Fa-Jun Nan b, Jing-Ya Li b, Jia Li b, , Bainian Feng a,c,
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a School of Pharmaceutical Science, Jiangnan University, Wuxi 214122, China
b State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
c Jiangsu Alpha Biopharmaceuticals, Inc., Wuxi 214122, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of bis-aromatic amides was designed, synthesized, and evaluated as a new class of inhibitors
with IC50 values in the micromolar range against protein tyrosine phosphatase 1B (PTP1B). Among them,
compound 15 displayed an IC50 value of 2.34 0.08 lM with 5-fold preference over TCPTP. More impor-
tantly, the treatment of CHO/HIR cells with compound 15 resulted in increased phosphorylation of insu-
lin receptor (IR), which suggested extensive cellular activity of compound 15. These results provided
novel lead compounds for the design of inhibitors of PTP1B as well as other PTPs.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 6 February 2014
Revised 5 March 2014
Accepted 7 March 2014
Available online 15 March 2014
Keywords:
Bis-aromatic amides
PTP1B inhibitors
Selectivity
Cellular activity
Structure–activity relationships (SARs)
Reversible protein tyrosine phosphorylation, catalyzed by the
opposing actions of protein tyrosine kinases (PTKs) and protein
tyrosine phosphatases (PTPs), is considered the key pathway for
controlling protein functions in living cells.1 Dysregulation of pro-
tein tyrosine kinases (PTKs) and protein tyrosine phosphatases
(PTPs) is linked to numerous human diseases, including cancer, dia-
betes, obesity, infection, autoimmune, and neuropsychiatric disor-
ders.2,3 Hence, PTKs and PTPs are emerging as high value targets
for therapeutic intervention.3–7 Many drug discovery programs
conducted to date have focused on the PTKs and more than a dozen
small molecule inhibitors targeting the kinases have reached the
market.8 However, the therapeutic benefits of modulating PTPs
are still underexplored despite the fact that several PTPs have been
identified as high value targets.9
Protein tyrosine phosphatase 1B (PTP1B) is prototypic member
of PTP family that appears to be involved in the regulation of several
cellular functions.10 Biochemical and genetic experiments have
established that PTP1B is a key negative regulator of insulin recep-
tor and leptin receptor-mediated signaling pathway and plays a
critical role in insulin and leptin signaling.11 Besides its central role
in the insulin cascade, PTP1B is involved in other important
pathways related with human breast and ovarian cancers.12,13 Con-
sequently, small molecule PTP1B inhibitors that not only serve as
powerful tools to define the physiological roles of PTP1B in vivo,
but also as excellent lead compounds for the development of new
therapeutic agents for type 2 diabetes mellitus, obesity, and cancer.
Various PTP1B inhibitors have been developed over the past dec-
ade.14–16 However, only two candidates have entered clinical trials
while no commercial drugs have been approved till date due mainly
to limited bioavailability.17–19 There are two significant challenges
to develop orally bioavailable, small molecular PTP1B inhibitors14
:
(1) PTP1B shares the close homology with other PTPs, for example,
T-cell protein tyrosine phosphatase (TCPTP) shares a structurally
very similar active site with PTP1B and about 80% homologous in
the catalytic domain, making it difficult to design inhibitors that
are specific for PTP1B,20 and (2) many small molecules that bind
with high affinity in active site are hydrophilic, and as a result they
have poor cell permeability. Therefore, imminent development of
potent and bioavailable PTP1B specific inhibitor remains necessary.
In order to search for new compounds with better PTP1B/TCPTP
inhibitory selectivity and potential bioavailability, benzidine
derivative 1, which has similar scaffold to hepatitis C virus NS5A
inhibitors,21 was identified as novel PTP1B inhibitor (IC50 = 19.27
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Corresponding authors. Tel./fax: +86 510 85329042 (W.-L.W. and B.F.); tel./fax:
+86 21 50800721 (J.L.).
1.80
lM) through high throughput screening of our compound
These authors contributed equally to this work.
collection (Fig. 1). This result provided us a chance to explore novel
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.