Design, synthesis, and biological evaluation of novel imidazo[1,2-a]pyridine derivatives as potent c-met inhibitors

Article abstract of DOI:10.1021/ml5004876

A series of imidazo[1,2-a]pyridine derivatives against c-Met was designed by means of bioisosteric replacement. In this study, a selective, potent c-Met inhibitor, 22e was identified, with IC₅₀ values of 3.9 nM against c-Met kinase and 45.0 nM

Full text of DOI:10.1021/ml5004876

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Letter
Design, Synthesis and Biological Evaluation of Novel
Imidazo[1,2-a]pyridine Derivatives as Potent c-Met Inhibitors
Chunpu Li, Jing Ai, Dengyou Zhang, Xia Peng, Xi Chen, Zhiwei Gao, Yi
Su, Wei Zhu, Yinchun Ji, Xiaoyan Chen, Mei-Yu Geng, and Hong Liu
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Design, Synthesis and Biological Evaluation of Novel Imid-
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azo[1,2-a]pyridine Derivatives as Potent c-Met Inhibitors
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†,ǁ
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Chunpu Li, Jing Ai, Dengyou Zhang, Xia Peng, Xi Chen, Zhiwei Gao, Yi Su, Wei Zhu,
‡
§
*,‡
*,†
Yinchun Ji, Xiaoyan Chen, Meiyu Geng and Hong Liu
†
‡
CAS Key Laboratory of Receptor Research, Division of Anti-Tumor Pharmacology, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, P. R. China
§
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, P. R. China
KEYWORDS: Receptor tyrosine kinase, c-Met inhibitor, imidazo[1,2-a]pyridine, metabolic stability
ABSTRACT: A series of imidazo[1,2-a]pyridine derivatives against c-Met was designed by means of bioisosteric replace-
ment. In this study, a selective, potent c-Met inhibitor, 22e was identified, with IC50 values of 3.9 nM against c-Met kinase
and 45.0 nM against c-Met-addicted EBC-1 cell proliferation, respectively. 22e inhibited c-Met phosphorylation and
downstream signaling across different oncogenic forms in c-Met over-activated cancer cells and model cells. 22e signifi-
cantly inhibited tumor growth (TGI = 75%) with good oral bioavailability (F = 29%) and no significant hERG inhibition.
Based on systematic metabolic study, the pathway of all possible metabolites of 22e in liver microsomes of different spe-
cies has been proposed, and a major NADPH-dependent metabolite 33 was generated by liver microsomes. To block the
metabolic site, 42 was designed and synthesized for further evaluation. Taken together, the imidazo[1,2-a]pyridine scaf-
fold showed promising pharmacological inhibition of c-Met and warrants further investigation.
Receptor tyrosine kinases (RTKs) have a critical role in
the development and progression of many types of can-
(SGX-523) is no longer in clinical development, because of
1
0
acute renal failure. Without any safety concerns, the
1
11
cer. The receptor tyrosine kinase c-Met is expressed
clinical study of inhibitor 4 (PF-04217903) was prema-
2
mainly by epithelial cells of many organs. Activation of
turely discontinued. In addition, compounds 5 (AMG-
1
2
13
c-Met is regulated upon binding with its natural ligand,
337) and 6 (INC-280) were reported and have entered
3
hepatocyte growth factor (HGF), and interaction with
phase II clinical trials.
4
other membrane receptors. The normal functions of
Figure 1
HGF/c-Met pathway are largely restricted to embryogene-
5
Among the known c-Met inhibitors, bicyclic triazole-
based or triazine-based inhibitors demonstrated high c-
Met inhibitory potency and excellent selectivity against
other kinases. However, many projects of these inhibitors
sis, tissue injury repair and regeneration in adults.
Dysregulation of the HGF/c-Met pathway (through, e.g.,
c-Met transcriptional upregulation, MET gene amplifica-
tion or rearrangement, and activating mutations of MET
gene) can induce cell proliferation, invasion, migration,
and apoptosis avoidance, leading to tumor growth, angio-
in clinical or discovery development were stopped due to
9,10,14
toxicity or unknown reasons.
Thus, there is still a
3
need to discover new classes of inhibitors against c-Met
for the treatment of cancer patients. The publicly availa-
ble cocrystal structure of PF-04217903 within c-Met (PDB
3ZXZ) disclosed the binding mode of this kind of inhibi-
genesis and metastasis. Importantly, aberrant c-Met ac-
tivation observed frequently in many human solid tumors
and hematological malignancies is associated with poor
6
clinical outcomes. Furthermore, overactivation of c-Met
11
7
tors. Generally, the quinoline nitrogen atom participates
causes therapeutic resistance. For these reasons, c-Met
in a hydrogen bond with the hinge region residue Met-
has become an attractive target for cancer therapy.
1
160. The N-3 nitrogen of triazolopyrazine backbone
Recently, a numerous number of small molecule c-Met
formed a hydrogen bond with Asp-1222. Meanwhile, triaꢀ
zolopyrazine backbone play an important role in both c-
Met activity and kinase selectivity via the unique face-to-
face π-stacking interaction with the activation loop resi-
due Tyr-1230, and there is a positive correlation between
electron deficiency of bicyclic aromatic rings and the
inhibitors have been reported (Figure 1). Compound 1
8
(Crizotinib) developed by Pfizer is a potent c-Met/ALK
dual inhibitor that demonstrated marked efficacy for a
subset of non-small cell lung cancer (NSCLC) patients
with an EML4-ALK fusion gene. Phase I clinical trial of
9
inhibitor 2 (JNJ38877605) has been terminated because
11
strength of π−π interaction with Tyr-1230. The substitut-
of an increase in serum creatinine levels. Inhibitor 3
ed aryl/heteroaryl (e.g., 1-Methylpyrazole) on the back-
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bone reaches out into the solvent (Figure 2). Bioisosteric interaction with electron rich Tyr-1230, which is critical
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replacement is a powerful method for the identification of
novel chemical series in medicinal chemistry. Based on
the previous work by Merck, 8-fluoroimidazo[1,2-
a]pyridine has been established as a physicochemical
mimic of imidazo[1,2-a]pyrimidine, using both in silico
for c-Met inhibition. Compared with 15g, the binding
pose of 15c (Figure 3B) was entirely different since the
bulky C-8 CF3 substituent could not enter the inside
pocket, which could be the main reason for the loss in
inhibitory activity. Compared to 8-fluoroimidazo[1,2-
a]pyridine core (15g), the 8-chloroimidazo[1,2-a]pyridine
is more electron rich, leading to a decreased interaction
with Tyr-1230. Taken together, these results could give an
explanation to the different inhibition of these com-
pounds.
1
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and traditional techniques. To the best of our
knowledge, there are still no examples of using this strat-
egy to discover novel c-Met inhibitors. Hence, we tried to
replace the 8-position N atom with a C-F bond to mimic
the properties of N-8 atom, including electrostatic surface
and lipophilicity to keep the electron deficiency of bicy-
clic aromatic rings. Meanwhile, we tried to introduce Cl,
CN and CF3 on the imidazo[1,2-a]pyridine to evaluated
the effluence of the electron density of bicyclic aromatic
rings on c-Met inhibition. On the basis of the cocrystal
structural information and principles of bioisosterism, we
designed a novel imidazo[1,2-a]pyridine scaffold as cꢀMet
inhibitors. Herein, we describe our recent effort on the
synthesis and SARs of this series of compounds.
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Figure 3
Subsequently, the structure activity relationship at the
6
-position of the imidazo[1,2-a]pyridine scaffold was in-
vestigated (Table 2). Introduction of heteroaryl substitu-
ents (16a-c) displayed good c-Met inhibition. The pyridi-
nyl analog 16b, which incorporated a cyano group, was
more effective and the EBC-1 cell IC50 reached to 188.5
nM. Among the phenyl derivatives (16d-g), benzonitrile
analogs 16d and 16f demonstrated improved c-Met inhibi-
tion, with an EBC-1 cell IC50 of 106.7 and 145.0 nM, respec-
tively. These observations indicated that incorporation of
polar groups on 6-phenyl had a significant influence on
cellular activity. Encouraged by these results, analogs in-
corporated polar amide groups on 6-phenyl were pre-
pared for SAR exploration. 6-Benzamide analog 22a dis-
played 4-fold loss in cellular activity compared to 16d.
Derivatives bearing 4-fluoro-3-N-methylbenzamide (22b)
and 4-chloro-3-N-methylbenzamide (22c) groups dis-
played less potent c-Met inhibition than 22a. However,
derivatives bearing 3-methoxy-4-N-methylbenzamide
Figure 2
To achieve a structure−activity relationship (SAR) ex-
ploration, efficient synthetic routes were employed for
preparation of the analogues (Scheme 1 and 2 in Support-
ing Information).
These novel imidazo[1,2-a]pyridine derivatives against
c-Met have not been previously synthesized and evaluat-
ed; therefore, the initial goal was to identify the optimal
substituent. To identify potent c-Met inhibitors efficient-
ly, we initially selected 1-methylpyrazole as a substituent
at the C-6 position while varying the C-7 and C-8 substit-
uents (Table 1). The initial biochemical assay found that
compound 15a exhibited moderate activity with an enzy-
matic IC50 of 2.18 μM against c-Met. The activity did not
significantly change with the introduction of different
substituents at the C-7 or C-8 position (15b-15f). To our
delight, compound 15g exhibited c-Met inhibition with an
enzymatic IC50 of 7.8 nM and an EBC-1 cell IC50 of 0.27
μM, respectively. These encouraging results prompted us
to investigate the SAR for substituents on the pyrazole
while keeping the fluorine substitute at the C-8 position.
The incorporation of polar groups, such as an ethanolic
group (15h) and a piperidine group (15i) on the pyrazole
of 15g resulted in 1.2-fold and 5.4-fold loss of cellular po-
tency, respectively.
(22d) and 3-fluoro-4-N-methylbenzamide (22e) groups
exhibited remarkably improved cellular activity. In par-
ticular, compound 22e showed an enzymatic IC50 of 3.9
nM and good EBC-1 cell IC50 of 45.0 nM. These results
indicated that the 3-F and 3-OMe might be important for
c-Met inhibition.
Table 2
To further modulate physical chemical properties of
these inhibitors, substituted amides were introduced,
especially amides with polar groups such as basic amines
on their N-terminus (Table 3). Firstly, the N,N’-
disubstituted amide analogs were evaluated. Compounds
22f and 22g showed an EBC-1 cell IC50 of 405.5 and 868.9
nM respectively, suggesting that N-monosubstituents
were preferred here. Next, we investigated the influence
of mono-substitution of the N-terminus of the amide on
c-Met inhibition. For example, compound 22h, which
contained a morpholinoethyl group on the N-terminus of
the amide, demonstrated c-Met inhibition by 2-fold com-
pared with 22e, and there was no significant differences
between their EBC-1 activity. Replacement of the morpho-
linoethyl group with a non-cyclic dimethylaminoethyl
group (compound 22i, enzymatic IC = 2.4 nM and EBC-1
Table 1
To gain structural information for further optimization,
the 3D proposed binding modes of representative com-
pounds 15a, 15c, 15e and 15g were generated by docking
simulation (Figure 3). For each compound, the best pose
with the lowest binding energy was selected for further
16
17
analysis with Glide and PyMOL . The binding mode
indicated that compound 15g was bound to the active site
of c-Met in a similar to PF-04217903 (Figure 3A). The ni-
trogen of quinoline H-bonds well with the hinge region
Met-1160, whereas the N-1 nitrogen of the imidazo[1,2-
a]pyridine scaffold formed a hydrogen bond with Asp-
5
0
cell IC50 = 49 nM) slightly improved the cell inhibitory
activity. Compound 22j, with a longer C-chain of the am-
ide, reduced EBC-1 cell inhibitory activity by 3-fold. We
also investigated the SARs of the compounds by restrict-
1
222. In addition, imidazo[1,2-a]pyridine core kept a π−π
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(Figures S4 in Supporting Information). Collectively, the-
ing the side-chain conformation at the N-terminus of the
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amides (compounds 22k, 22l and 22o). When the N-
terminus of the amide was replaced with a piperidin-2-
ylmethyl group (compound 22k, EBC cell IC50 = 276.8 nM)
se results indicated that 22e inhibited the metastasis and
invasiveness phenotype evoked by the HGF/c-Met axis in
cancer.
or a piperidin-3-yl group (compound 22l, EBC cell IC50
=
Upon HGF stimulation, c-Met induces several biologi-
cal responses that collectively give rise to a program
known as invasive growth, which is pivotal to drive cancer
1
37.5 nM), c-Met inhibition was 5.5- and 4.3-fold more
potent than 22e, respectively. In addition, we investigated
compounds that contained an aryl group or a heteroaryl
group on the N-terminal side of the amides. Compound
22
cell invasion and metastasis. Thus, we investigated
whether 22e inhibited c-Met-mediated invasive growth.
Exposure to 22e inhibited branching morphogenesis in
MDCK cells (Figures S5 in Supporting Information), in-
dicating the 22e inhibited HGF-induced c-MET-mediated
invasive growth.
22m showed sharply decreased c-Met cell inhibition,
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which could be caused by an intramolecular hydrogen
bond interaction between the hydrogen atom of the am-
ide and the pyridine nitrogen. The potency of compound
2
2n against EBC-1 cell proliferation is comparable to that
of optimal compound 22e.
Table 3
The pharmacokinetic (PK) profiles of the selected com-
pound 22e were assessed in Sprague-Dawley (SD) rats
(Table S2 in Supporting Information). Compound 22e
Given its promising enzymatic and cellular potency, 22e
was selected as the lead compound for subsequent evalua-
tion. In contrast to its high potency against c-Met, 22e
had barely any inhibitory effect on the other 21 tested
kinases, including c-Met family member RON and highly
homologous kinases Axl, c-Mer, Tyro-3 (IC >10 μM), in-
showed a high area under the curve (AUC0-∞) when dosed
orally. The half-life and the absolute oral bioavailability of
compound 22e were 1.17 h and 29.4%, respectively.
We used the ultra-performance liquid chromatography
quadrupole time of flight mass spectrometry (UPLC-
qTOF-MS) method to identify the possible metabolites of
22e in liver microsomes of different species. We have
proposed the metabolism pathway and all the metabolites
of 22e (Scheme 3a in Supporting Information). In view of
the result that the major oxidant metabolism take place in
the benzyl position of this scaffold, we speculated that
metabolite 33 was the major metabolite of 22e after incu-
bation in mice, dog, monkey, and human liver micro-
somes, except rat liver microsomes (Table S3 in Support-
ing Information).
5
0
dicating that 22e was a selective c-Met inhibitor (Table S1
in Supporting Information).
As shown in Figure S1 (See Supporting Information),
22e inhibited the phosphorylation of c-Met and its key
downstream molecules Akt and Erk in a dose-dependent
manner in representative cancer or model cell lines (EBC-
1
, MKN45, BaF3/TPR-Met cells). These results suggested
that 22e suppressed c-Met signaling across different on-
cogenic forms in c-Met over-activated cells.
22e significantly inhibited cell proliferation of EBC-1,
MKN-45, SNU-5, and BaF3/TPR-Met cells, which are
characterized by a c-Met-dependent cell growth, with an
IC50 value of 45.0 to 203.2 nM (Table 4), however, 22e
barely inhibited these other cell lines, of which had Met
low expression or activation (IC >50 μM) (Figure S2A in
The IC value of compound 22e on hERG was 93.56 μM
5
0
TM
using a FluxOR thallium assay. Thus, 22e did not show
significant hERG inhibition.
To assess the in vivo antitumor efficacy of 22e, an EBC-1
xenograft model specifically driven by MET amplification
was chosen. After 21-days of 22e (methanesulfonic salt)
oral administration, dose-dependent tumour growth in-
hibition was observed in 22e treated groups, with an in-
hibitory rate of 75.0% (P<0.05) and 62.9% (P<0.05) at
doses of 100 mg/kg and 50 mg/kg, respectively (Figure 4).
No significant weight losses were observed (data not
shown).
5
0
Supporting Information). c-Met inhibition blocks cell
1
8
proliferation via arresting cells in G1/S phase. 22e in-
duced a G1/S phase arrest in the EBC-1 cells, with 81.84%
of the cell population in G1 phase in the presence of 1 μM
22e (versus 52.95% in the vehicle control group) (Figures
S2B-C in Supporting Information).
Table 4
Figure 4
The HGF/c-Met axis activation promotes cell invasion
Futhermore, we synthesized the major metabolite 33 for
further investigation (Scheme 3b in Supporting Infor-
mation), however, it had no significant inhibitory effect
19
and migration to allow cancer metastasis. 22e inhibited
the migration of HGF-induced NCI-H441 cells, and almost
completely blocked the cell migration phenotype at a
dose of 500 nM (Figures S3A, S3C in Supporting Infor-
mation). Further, 22e strongly suppressed the invasion of
HGF-induced NCI-H441 cell (Figures S3B, S3D in Sup-
porting Information).
on c-Met-dependent cell proliferation (enzymatic IC50
=
82.9±25.9 nM and EBC-1 cell IC50 = 3022.3 nM). Since we
have identified metabolic hot spots of 22e, we designed
and synthesized compound 42 (Scheme 4 in Supporting
Information), which bears a cyclopropyl at the linker of
23
Cell scattering induced by HGF/c-Met activation is a
this scaffold that might block the metabolic site. Even
20
hall-mark of cancer invasiveness and metastasis. Upon
HGF stimulation, epithelial cells undergo colony dispersal
though 42 demonstrated potent inhibitory effect on c-Met
kinase and c-Met-dependent cell viability (enzymatic IC50
21
and become migratory, fibroblast-like cells. 22e treat-
ment reduced HGF-induced cell scattering of MDCK ca-
nine kidney epithelial cells in a dose-dependent manner
= 23.5 nM and EBC-1 cell IC = 60.0 nM), the in vivo anti-
50
tumor efficacy of 42 was disappointing. Further optimiza-
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(orange) and 15g (purple) in the same cavity along with PF-
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04217903 (green) as the reference molecule.
tumor efficacy are ongoing in our laboratory.
In conclusion, a series of novel imidazo[1,2-a]pyridine
derivatives were designed, synthesized and evaluated as c-
Met inhibitors by means of bioisosteric replacement. SAR
exploration led to the identification of a potent, selective
c-Met inhibitor 22e. 22e showed strong potency against c-
Met kinase, inhibited c-Met phosphorylation and down-
stream signaling across different oncogenic forms in c-
Met over-activated cancer cells and model cells. Further-
more, 22e treatment resulted in significant antitumor
activity in c-Met-driven EBC-1 xenografts. Compound 42
was designed by means of metabolite identification. Fur-
ther optimizations are currently under investigation.
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Figure 4. 22e inhibits tumor growth in EBC-1 xenografts. 22e
in the methanesulfonic acid salt form or JNJ38877605 was
administered orally once daily for 3 weeks after the tumor
F
Cl
F
N
N
N
F
3
volume reached 100 to 150 mm . The results are expressed as
N
N
HN
O
Cl
N
N
the mean±SEM (drug-treated group, n = 6; vehicle group,
n=12). *p<0.05, *** p<0.001 vs control group, determined
using Student’s t test.
N
N
N
NH
2
1
,Crizotinib
2, JNJ38877605
c-Met IC50 = 1 nM
c-Met IC50 = 8 nM
Table 1. SAR of substituents on the imidazo[1,2-
a]pyridine scaffold.
N
N
N
N
S
HO
N
N
N
N
N
N
N
N
N
N
N
3
, SGX-523
4, PF-4217903
c-Met K = 4 nM
c-Met IC50 = 4 nM
i
O
N
b
O
F
IC50
EBC-1
N
N
Compd
R
1
R
2
R
3
a
N
(nM)
IC50 (μM)
N
S
NH
H
N
N
c
N
15a
15b
Cl
H
H
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
2180±120
24.5% @ 1 μM
9.6% @ 1 μM
5.9% @ 1 μM
34.5% @ 100 μM
33.3% @ 100 μM
7.8±0.3
ND
N
N
N
N
N
Cl
H
ND
ND
6
, INC-280
c-Met IC50 = 0.13 nM
5, AMG-337
c-Met IC50 = 6 nM
15c
15d
15e
15f
CF
H
3
CF
H
3
ND
Figure 1. Representative c-Met inhibitors.
CN
H
F
ND
CN CH
ND
15g
H
H
CH
0.27±0.05
1
5h
5i
F
3.2±0.3
11.1±1.7
0.34±0.03
1.46±0.02
1
F
H
a
IC50 values were calculated by the Logit method from the results of
at least two independent tests with eight concentrations each and
expressed as mean ± SD, c-Met IC50 of Crizotinib = 2.4±0.1 nM, c-
b
Met IC50 of JNJ38877605 = 1.8±0.3 nM; EBC-1: human non-small-
cell lung cancer cell line that expresses elevated levels of constitu-
c
tively active c-Met; not detected.
Figure 2. Design of the imidazo[1,2-a]pyridine scaffold.
Table 2. SAR at the 6-position of the imidazo[1,2-
a]pyridine scaffold.
a
b
Compd
6a
R
IC50(nM)
EBC-1 IC50(nM)
Figure 3. The binding model comparison of designed com-
pounds with PF-04217903. (A) Binding pose of compound 15g
1
4.3±0.6
443.6±6.9
(
purple) with c-Met; (B) Overlay of 15a (blue),15c (pink),15e
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6b
5.6±1.9
188.5±23.3
22j
3.4±1.1
161.3±2.2
1
2
3
4
5
6
7
8
9
1
6c
14.5±0.2
1.8±0.3
224.6±75.1
106.7±15.3
22k
0.7±0.2
276.8±0.7
16d
22l
0.9±0.3
8.3±1.6
4.7±0.1
4.2±0.7
137.5±1.3
5549.9±839.2
53.6±18.7
1
6e
2.7±0.4
3.3±0.2
790.1±194.1
145.0±39.2
22m
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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32
33
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45
46
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60
1
6f
22n
1
6g
2.8±0.5
9.7±0.7
407.4±164.0
22o
70.5±37.5
16h
1475.0±260.0
Compd
Structure
2
2a
6.0±0.9
400.0±159.5
82.9±
2
2b
16.2±1.6
12.8±0.2
10.6±0.2
3.9±0.7
246.4±86.3
946.4±322.4
59.6±17.7
33
3022.3±432.8
60.0±7.2
25.9
2
2c
23.5±
42
4.6
2
2d
a
IC50 values were calculated by the Logit method from the results of
at least two independent tests with eight concentrations each and
expressed as mean ± SD, c-Met IC50 of Crizotinib = 2.4±0.1 nM, c-
2
2e
45.0±12.7
b
Met IC50 of JNJ38877605 = 1.8±0.3 nM; EBC-1: human non-small-
cell lung cancer cell line that expresses elevated levels of constitu-
tively active c-Met.
a
IC50 values were calculated by the Logit method from the results of
at least two independent tests with eight concentrations each and
expressed as mean ± SD, c-Met IC50 of Crizotinib = 2.4±0.1 nM, c-
Table 4. Effects of 22e on cell proliferation
b
Met IC50 of JNJ38877605 = 1.8±0.3 nM; EBC-1: human non-small-
cell lung cancer cell line that expresses elevated levels of constitu-
tively active c-Met.
a
IC50 (nM)
EBC-1
22e
JNJ38877605
Crizotinib
21.8±6.5
45.0±12.7
90.9±17.4
70.2±19.6
203.2±4.4
9.5±2.0
10.9±0.4
15.8±3.2
17.6±2.2
Table 3. SAR of substituents on the amides.
MKN-45
38.1±8.8
20.4±14.4
127.4±8.1
SNU-5
BaF3/TPR-Met
a
The IC50 values are shown as the mean±SD (nM) from three sepa-
rate experiments.
IC50
nM)
b
ASSOCIATED CONTENT
Supporting Information.
Synthetic procedures and analytical data for compounds
reported in this letter and procedures for in vitro and in vivo
assays. This material is available free of charge via the Inter-
net at http://pubs.acs.org.
Compd
R
a
EBC-1 IC50(nM)
(
22f
21.4±2.0
39.1±3.4
2.0±0.3
2.4±0.1
405.5±155.6
868.9±22.8
52.0±15.6
22g
AUTHOR INFORMATION
Corresponding Author
22h
*
*
5
(H.L.) E-mail: hliu@simm.ac.cn. Phone: +86-21-50807042
(M.G.) E-mail: mygeng@simm.ac.cn. Phone: +86-21-
0806600-2426
22i
49.0±19.4
Author Contributions
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ǁ
by aldehyde oxidase and the toxicological implications. Drug
Metab. Dispos. 2010, 38, 1277-1285.
(
C.L., J.A. and D.Z.) These authors contributed equally to
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this work.
(11) Cui, J. J.; McTigue, M.; Nambu, M.; Tran-Dube, M.; Pairish,
M.; Shen, H.; Jia, L.; Cheng, H.; Hoffman, J.; Le, P.; Jalaie, M.;
Goetz, G. H.; Ryan, K.; Grodsky, N.; Deng, Y. L.; Parker, M.;
Timofeevski, S.; Murray, B. W.; Yamazaki, S.; Aguirre, S.; Li, Q.;
Zou, H.; Christensen, J. Discovery of a novel class of exquisitely
selective mesenchymal-epithelial transition factor (c-MET) pro-
tein kinase inhibitors and identification of the clinical candidate
Funding Sources
We gratefully acknowledge financial support from the Na-
tional Natural Science Foundation of China Grants (91229204
and 81220108025), Major Project of Chinese National Pro-
grams for Fundamental Research and Development
(
2015CB910304), National High Technology Research and
2-(4-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-
Development Program of China (2012AA020302), National
Basic Research Program of China (2012CB518005), National
S&T Major Projects (2012ZX09103101-072, 2014ZX09507002-
yl)-1H-pyrazol-1 -yl)ethanol (PF-04217903) for the treatment of
cancer. J. Med. Chem. 2012, 55, 8091-8109.
0
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12) Clinical trial data: https://www.clinicaltrials.gov/ct2/show/
NCT02016534.
13) Clinical trial data: https://www.clinicaltrials.gov/ct2/show/
001, and 2013ZX09507-001).
(
Notes
NCT01737827.
The authors declare no competing financial interest.
(14) Clinical trial data: https://www.clinicaltrials.gov/ct2/show/
NCT00706355.
ABBREVIATIONS
(15) Humphries, A. C.; Gancia, E.; Gilligan, M. T.; Goodacre, S.;
Hallett, D.; Merchant, K. J.; Thomas, S. R. 8-Fluoroimidazo[1,2-
a]pyridine: synthesis, physicochemical properties and evaluation
as a bioisosteric replacement for imidazo[1,2-a]pyrimidine in an
allosteric modulator ligand of the GABA A receptor. Bioorg. Med.
Chem. Lett. 2006, 16, 1518-1522.
c-Met, mesenchymal-epithelial transition factor; ALK, ana-
plastic lymphoma kinase; SARs, structure-activity relation-
ships; AUC, area under curve.
(
(
16) Glide, version 5.5, Schrödinger, LLC, New York, NY, 2009.
17) PyMOL, Version 1.4.1, Schrödinger, LLC, New York, NY,
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Design, Synthesis and Biological Evaluation of
Novel Imidazo[1,2-a]pyridine Derivatives as Po-
tent c-Met Inhibitors
‖
‖
‖
Chunpu Li, Jing Ai, Dengyou Zhang, Xia Peng, Xi
Chen, Zhiwei Gao, Yi Su, Wei Zhu, Yinchun Ji,
Xiaoyan Chen, Meiyu Geng*, and Hong Liu*
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