Scaffold hopping approach to a new series of smoothened antagonists

Article abstract of DOI:10.1016/j.bmcl.2014.03.079

The hedgehog (Hh) signaling pathway is a key regulator during embryonic development, while in adults, it has limited functions such as stem cell maintenance and tissue repair. The aberrant activity of the Hh signaling in adults has been linked to numerous human cancers. Inhibition of Hh signaling therefore represents a promising approach toward novel anticancer therapies. The Smoothened (Smo) receptor mediates Hh signaling. Here we report a new series of Smo antagonists which were obtained by a scaffold hopping strategy. Compounds from this new scaffold demonstrated decent inhibition of Hh pathway signaling. The new scaffold can serve as a starting point for further optimization.

Full text of DOI:10.1016/j.bmcl.2014.03.079

Bioorganic & Medicinal Chemistry Letters 24 (2014) 2300–2304
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Scaffold hopping approach to a new series of smoothened
antagonists
Wenfeng Lu a, , Delong Geng a, , Zhijian Sun b, Zhaohui Yang a, Haikuo Ma a, Jiyue Zheng a, Xiaohu Zhang a,
⇑
a Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Su Zhou, Jiangsu 215021,
PR China
b BeiGene (Beijing) Co., Ltd, No. 30 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The hedgehog (Hh) signaling pathway is a key regulator during embryonic development, while in adults,
it has limited functions such as stem cell maintenance and tissue repair. The aberrant activity of the Hh
signaling in adults has been linked to numerous human cancers. Inhibition of Hh signaling therefore rep-
resents a promising approach toward novel anticancer therapies. The Smoothened (Smo) receptor medi-
ates Hh signaling. Here we report a new series of Smo antagonists which were obtained by a scaffold
hopping strategy. Compounds from this new scaffold demonstrated decent inhibition of Hh pathway sig-
naling. The new scaffold can serve as a starting point for further optimization.
Received 11 December 2013
Revised 13 March 2014
Accepted 25 March 2014
Available online 3 April 2014
Keywords:
Hedgehog pathway
Smoothened
Antagonist
Ó 2014 Elsevier Ltd. All rights reserved.
GPCR
Scaffold hopping
Cancer therapy
The hedgehog (Hh) signaling pathway is a key developmental
pathway which regulates patterning, growth and cell migration
during embryonic development, but in adults it is limited to tissue
maintenance and repair. Under normal conditions, the endogenous
ligands sonic hedgehog, Indian hedgehog and desert hedgehog
bind to their receptor Patched (Ptch), relieving the inhibitory effect
of Ptch on Smoothened (Smo). Smo activation triggers a series of
events which ultimately lead to specific gene expression mediated
by the Gli family transcription factors.1 Aberrant Hh signaling has
been linked to numerous human cancers. Mutational inactivation
of the inhibitory pathway components such as Ptch leads to consti-
tutive ligand-independent activation of the Hh signaling pathway,
resulting in cancers such as basal cell carcinoma and medulloblas-
toma.2 Ligand-dependent activation of Hh signaling is involved in
prostate cancer, pancreatic cancer, breast cancer and some blood
cancers.3 Therefore, inhibition of aberrant Hh signaling represents
a promising approach toward novel anticancer therapy.4
clinical development.7 Numerous synthetic Smo antagonists had
been reported in recent years.8 The most advanced in the class,
GDC-0449 (Vismodegib, Fig. 1), was approved by FDA in January
2012 for the treatment of basal cell carcinoma which was not
suitable for operation.9 This approval showcased the first embry-
onic pathway inhibitor for the treatment of human cancer. Other
Smo antagonists are in different stages of development (Fig. 1).
We have investigated numerous templates in pursuit of novel
Smo receptor antagonists. Both GDC-04498c and NVP-LDE2258h
were the results of optimization campaigns based on initial screen-
ing hits. The central amide bonds were reversed, yet both
molecules maintained excellent potency. This observation
indicated that the central amides were place-holders, unlikely to
have participated in significant interactions with the Smo receptor.
This assumption was reinforced by Pfizer compound 110 (Fig. 2)
and a series of Amgen compounds.8g GDC-0449 possessed all
sp2-hybridized carbons, resulting in
a high melting point
Cyclopamine (Fig. 1), a naturally occurring alkaloid, was the
first reported Hh signaling pathway inhibitor,5 and it was later
identified as a Smo antagonist.6 A cyclopamine derivative, IPI-
926 (Fig. 1), which demonstrated better potency, stability and
other pharmaceutical properties than cyclopamine, had entered
(264 °C) and poor solubility (9.5 g/mL). Enhanced solubility was
l
achieved by adding an ortho-chloro group to the right side ring
to introduce tilt and reduce planarity of the aryl amide.8c It is well
documented in the literature that planarity and molecular
topology have significant impacts on absorption, metabolism and
toxicity.11 In order to improve the physical–chemical properties,
we proposed introducing the saturation ring as the place-holder
(introducing sp3-hybridized carbons, reducing planarity), as fea-
tured in compound 1. We also proposed tying the long tail featured
⇑
Corresponding author. Tel./fax: +86 512 65880380.
E-mail address: xiaohuzhang@suda.edu.cn (X. Zhang).
These authors contributed equally to this Letter.
http://dx.doi.org/10.1016/j.bmcl.2014.03.079
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

W. Lu et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2300–2304
2301
HN
H
HN
H
Cl
O
Cl
H
O
O
H
N
H
N
H
H
O
O
H
H
H
S
S
O
H
N
H
O
H
HO
GDC-0449
Vismodegib
Cyclopamine
IPI-926
CN
O
H
N
N
O
H
O
N
N
N
N
H
N
H
N
N
O
N
N
F3CO
N
N
N
H
O
O
PF-04449913
MK-5710
NVP-LDE225
Figure 1. Smoothened antagonists in advanced development.
Cl
Cl
N
N
NH2
H
N
N
NHTs
O
Cl
d
O
a
b, c
N
N
N
N
N
H
CF3
N
37
N
5
38
S
Cl
O
O
N
H
O
N
GDC-0449
e
N
N
N
N
40
R
N
CF3
N
N
N
HN
39
new template
H
O
O
H
N
N
O
R
f,g
h
O
e
N
N
S
N
38
43, 44
N
N
42a,b
N
R
1
O
HN
41a,b
Figure 2. Scaffold hopping approach to a novel series of smoothened antagonists.
41a: R
41b: R
O
in compound 1 to decrease rotatable bonds as a way to enhance
absorption and metabolic stability.12 The scaffold hopping strategy
led us to a novel template shown in Figure 2.
The general synthetic route used to prepare compounds 9–36
was shown in Scheme 1. Commercially available pyrazin-2-amine
5 was reacted with ethyl 3-bromo-2-oxopropanoate in DME at
room temperature and then refluxed in EtOH to give intermediate
6. Hydrogenation of intermediate 6 under Pd/C with Boc2O/EtOH
provided intermediate 7. Removal of the Boc-protecting group of
Scheme 2. Reagents and conditions: (a) TsCl, pyridine, rt, 80 min, 72%; (b)
2-iodoacetamide, DMF, rt, 28 h, 64%; (c) trifluoroacetic anhydride, DCM, reflux,
2 h, 97%; (d) 10% Pd/C, H2, MeOH, rt, 10 h, 25%; (e) Compound 4, CsF, DMSO, 120 °C,
48 h, 18–26%; (f) NH4OH, MeOH, 70 °C, 6 h, 44%; (g) corresponding acid, HATU,
DIPEA, DMF, rt, 24 h, 44–52%; (h) PtO2, H2, MeOH, rt, 48 h, 73%.
intermediate 7 in the presence of HCl/EtOAc led to intermediate
8, which was used to displace the 2-position chlorine of bipyridine
4 to yield ester 9. Compound 4 was obtained by Suzuki coupling of
HO
OH
B
Cl
Cl
a
N
Cl
N
2
Br
N
N
3
Cl
4
N
NH2
O
O
N
N
c
b
RN
N
e
N
N
N
OEt
R = Boc
R = H
OEt
7
8
6
5
d
Cl
Cl
N
N
O
f
N
O
g
N
N
N
N
11-32
36
N
N
N
OEt
OH
10
9
N
N
BocN
BocN
h
i, j
d,e
7
N
N
33
N
OH
35
O
d,e
34
Scheme 1. Reagents and conditions: (a) Pd(dppf)Cl2, K3PO4Á3H2O, dioxane, H2O, 110 °C, 16 h, 41%; (b) ethyl 3-bromo-2-oxopropanoate, DME, rt, 2.5 h, then EtOH, reflux, 2.5 h,
27%; (c) 10% Pd/C, EtOH, Boc2O, H2, 24 h, 63%; (d) HCl/EtOAc, rt, 3 h, 83–95%; (e) compound 4, CsF, DMSO, 120 °C, 48 h, for 9, 85%; for 34, 16%; (f) LiOH, THF, H2O, rt, 12 h, 70%;
(g) HATU, DIPEA, DMF, rt, 16 h, for 11–28, 26–72%; alcohol, SOCl2, reflux for 29 (45%) and 30 (36%); DCC, HOBt, DMAP, DCM, 6–36 h for 31 (25%) and 32 (66%); (h) LiAlH4, THF,
0 °C, 30 min, 70%; (i) MsCl, TEA, DCM, rt, 30 min; (j) morpholine, Na2CO3, ACN, 100 °C, 2 h, two steps, 43%.

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W. Lu et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2300–2304
Table 1
SAR of designed compounds
Cl
N
N
N
R
N
N
a
a
Compound
R
hSMO IC50
(lM) SEM
Compound
R
hSMO IC50 (lM) SEM
O
O
O
O
9
0.69 0.13
>10
24
25
26
0.087 0.016
0.44 0.02
0.42 0.16
O
N
H
F
F
10
11
OH
N
H
O
F
O
O
2.7 1.4
N
H
N
H
F
O
O
O
O
12
13
14
15
1.3 0.09
0.52 0.03
4.1 2.1
27
28
29
30
0.27 0.04
0.20 0.07
0.38 0.21
0.27 0.17
N
H
N
H
N
O
O
O
N
N
H
N
H
OH
N
N
O
O
0.27 0.03
O
O
O
O
16
17
0.79 0.36
>10
31
32
0.74 0.46
0.96 0.14
N
N
O
O
O
OH
O
O
OH
N
18
19
>10
34
4.1 0.39
OH
N
O
N
0.55 0.06
36
40
0.91 0.23
O
O
F
H
N
F
F
N
N
20
21
1.2 0.46
1.5 0.70
1.8 0.70
O
O
OH
O
H
N
43
44
0.89 0.03
NH
H
N
O
O
O
22
23
0.30 0.01
0.35 0.16
0.65 0.10
N
H
O
Vismodegib
0.023 0.016b
N
H
F
a
Inhibition of luminescence signaling in NIH3T3-GRE-Luc reporter gene assay with 10 nM SAG as the Hh pathway agonist. Data are expressed as geometric mean values of
at least two runs the standard error measurement (SEM).
b
Vismodegib was run as standard in each assay. Data are expressed as geometric mean values of seven runs the standard error measurement (SEM).
2-bromo-3,5-dimethyl pyridine and 2,5-dichloropyridin-4-
ylboronic acid with Pd(dppf)Cl2 and K3PO40Á3H2O in dioxane and
water. Hydrolysis of ester 9 in the presence of LiOH/THF/H2O
yielded acid 10, which was coupled with corresponding amines
or alcohols to provide amides 11–28 or esters 29–32, respectively.
In order to obtain compounds 34 and 36, intermediate 7 was
selectively reduced with LiAlH4 to give alcohol 33, which was
de-protected and then used to substitute 2-position chlorine of
bipyridine 4 under CsF/DMSO at 120 °C to provide compound 34.
The alcohol 33 was mesylated and then substituted with

W. Lu et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2300–2304
2303
morpholine to give intermediate 35, which was de-protected and
then used to substitute 2-position chlorine of bipyridine 4 to pro-
vide compound 36.
In summary we have utilized a scaffold hopping strategy to de-
sign and synthesize a new series of Smo inhibitors. Compounds
from this new scaffold demonstrated decent inhibition of hedge-
hog pathway signaling. The new scaffold can serve as a starting
point for further optimization.
Synthesis of compounds 40, 43 and 44 was described in
Scheme 2. The key intermediate 38 was prepared via a three-step
reaction, starting from the tosylation of commercially available
pyrazin-2-amine 5 with TsCl to yield intermediate 37, which was
then reacted with 2-iodoacetamide, followed by cyclization with
trifluoroacetic anhydride in DCM at reflux temperature. Hydroge-
nation of intermediate 38 in the presence of Pd/C/MeOH led to
intermediate 39, which was used to substitute the 2-position chlo-
rine of intermediate 4 under CsF/DMSO at 120 °C to yield com-
pound 40. Hydrolysis of intermediate 38 in the presence of
NH4OH/MeOH followed by coupling with acids provided amides
41a and 41b. Hydrogenation of amides 41a and 41b in the pres-
ence of PtO2 with MeOH yielded intermediates 42a and 42b, which
were used to displace the 2-position chlorine of bipyridine 4 under
CsF/DMSO at 120 °C to yield compounds 43 and 44.
Acknowledgments
The work was supported by National Natural Science Founda-
tion of China (Grant No. 81273372), China Postdoctoral Science
Foundation (2013M541729), BM2013003, and PAPD (A Project
Funded by the Priority Academic Program Development of Jiangsu
Higher Education Institutions).
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The SAR was summarized in Table 1.
The inhibitory effects of the synthesized compounds on the Hh
signaling pathway were tested using a cell based NIH3T3-GRE-
Luc reporter gene assay with 10 nM SAG as the Hh pathway ago-
nist.8a,13 The simplest compound of this series of analogues, com-
pound 10, was virtually inactive (>10 lM). This was not
unexpected since the carboxylic acid was a dramatic move away
from the usual SAR. Simple amides 11, 12 and 13 demonstrated
moderate to decent potencies (2.7, 1.3, 0.52
Addition of a polar hydroxyl and capping the NH of the amide did
not improve activity (compound 14, 4.1 M). However, when sec-
ondary amine pyrrolidine was used to form the amide, a compound
with respectful activity was achieved (compound 15, 0.27 M). At-
lM, respectively).
l
l
tempts to further improve the activity by applying larger amines or
amines with polar functional groups were not successful as com-
pounds 16–21 were not as potent as compound 15. Ethyl ester ana-
logue 9 demonstrated decent potency (0.69
further improved when the ethyl was changed to isopropyl and
methylcyclopropyl (compound 29 and 30, 0.38 and 0.27 M,
respectively). Unfortunately, the trend did not hold as larger esters
31 and 32 were less potent (0.74 and 0.96 M, respectively). At-
lM), which were
l
l
tempts to increase the flexibility of this tail region were made by
reducing the amide carbonyl to methylene, but the increased flex-
ibility failed to yield improved potency as both compounds 34
and 36 were less active. Through a different synthetic approach,
the ‘reversed’ amide template was achieved (compounds 40, 43
and 44). Trifluoacetamide 40 was moderately active (1.8
compounds 43 and 44 demonstrated decent activity (0.89
0.65 M, respectively). When simple aniline was applied to form
the carboxamide, a compound with respectful activity was ob-
tained (compound 22, 0.30 M). Addition of an ortho-fluorine or a
para-fluorine had no significant impact on the activity (compounds
23 and 25, 0.35 and 0.44 M, respectively), however, addition of a
meta-fluorine yielded the most potent analogue (compound 24,
0.087 M), which demonstrated activity within reachable range
of Vismodegib. Di-substituted fluorine analogue did not help with
activity improvement (compound 26, 0.42 M). Hetero atoms were
lM), while
lM,
l
l
l
l
l
incorporated into aniline and both resulting amino-pyridine ana-
logues demonstrated respectful activity (compounds 27 and 28,
0.27 and 0.20
signed from a template hopping strategy provided numerous active
compounds (e.g., 15, 24, 28 and 30, 0.27 M, 0.087 M, 0.20
and 0.27 M, respectively). Although the potency was not yet com-
parable to that of the marketed drug Vismodegib (0.026 M), these
lM, respectively). Overall, this novel scaffold de-
l
l
lM
l
l
results were nonetheless encouraging and worthy of further inves-
tigation in light of the large structural changes involved. Explora-
tion of other regions of this novel template is ongoing in our lab
and the results will be reported in due course.
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