Discovery of imidazopyridine derivatives as highly potent respiratory syncytial virus fusion inhibitors

Article abstract of DOI:10.1021/acsmedchemlett.5b00008

A series of imidazolepyridine derivatives were designed and synthesized according to the established docking studies. The imidazopyridine derivatives were found to have good potency and physical-chemical properties. Several highly potent compounds such as 8ji, 8jl, and 8jm were identified with single nanomolar activities. The most potent compound 8jm showed an IC₅₀ of 3 nM, lower microsome clearance and no CYP inhibition. The profile of 8jm appeared to be superior to BMS433771, and supported further optimization.

Full text of DOI:10.1021/acsmedchemlett.5b00008

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Letter
Discovery of Imidazopyridine Derivatives as Highly
Potent Respiratory Syncytial Virus Fusion Inhibitors
Song Feng, Di Hong, Baoxia Wang, Xiufang Zheng, Kun Miao, Lisha
Wang, Hongying Yun, Lu Gao, Shuhai Zhao, and Hong C Shen
ACS Med. Chem. Lett., Just Accepted Manuscript • Publication Date (Web): 25 Jan 2015
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Discovery of Imidazopyridine Derivatives as Highly Potent Respira-
tory Syncytial Virus Fusion Inhibitors
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Song Feng*†, Di Hong†, Baoxia Wang†, Xiufang Zheng†, Kun Miao†, Lisha Wang‡, Hongying
Yun†, Lu Gao§, Shuhai Zhao†, Hong C. Shen†
†
‡
§
Medicinal Chemistry, Molecular Design and Chemical Biology, Infectious Diseases, Pharmaceutical Research
and Early Development, Roche Innovation Center Shanghai, Building 5, Lane 720, Cai Lun Road, Shanghai 201203,
China
KEYWORDS: Respiratory Syncytial Virus (RSV), Virus, antiviral, Fusion inhibitors, Imidazopyridine, Heterocycle
ABSTRACT: A series of imidazolepyridine derivatives were designed and synthesized according to the established dock-
ing studies. The imidazopyridine derivatives were found to have good potency and physical-chemical properties. Several
highly potent compounds such as 8ji, 8jl, and 8jm were identified with single nanomolar activities. The most potent
compound 8jm showed an IC50 of 3 nM, lower microsome clearance and no CYP inhibition. The profile of 8jm appeared
to be superior to BMS433771, and supported further optimization.
Human respiratory syncytial virus (RSV) is one of the
most important respiratory pathogens that cause lower
respiratory tract infections such as bronchiolitis and
pneumonia in infants and young children, resulting in up
to 125,000 hospitalizations annually in the United States1.
The mortality rate among children admitted to hospital is
approximately 3% for those with heart and lung problems
and up to 1% for those without these risk factors2,3. In
adults and the elderly, RSV pneumonia is increasingly
recognized as a significant cause of morbidity and mortal-
ity, being associated with more than 17,000 deaths annu-
alone for virus binding and cell entry11. The associated G
glycoprotein appears to facilitate viral attachment. This
pivotal role for the fusion protein has inspired a number
of approaches over the years and led to compounds suita-
ble for clinical evaluation12.
Several chemical series have been reported as RSV fusion
inhibitors and two apparently progressed into early clini-
cal development. One Leading series is a class of benzim-
idazole pyridines13-16. The lead JNJ-2408068(1) demon-
strated nanomolar potency in RSV in vitro assays. TMC-
353121(2) was reported to access an additional binding
pocket in the binding space13-16, and displayed sub-
nanomolar RSV in vitro activity with an unusual lung tis-
sue residence half-life of 25 h. Another example of tricy-
clic imidazolines 3, was reported to inhibit RSV in cell
culture at 100-250 ng/mL15,16. Recently, GS-5806(4) was
described as a novel RSV fusion inhibitor achieved proof-
of-concept in human RSV challenge studies17. In addition,
VP-14637(6) was in Phase I trials prior to a decision not to
develop it further, in part due to development costs18.
RFI-641(7) was in Phase II clinical trials in 2000-2001 for
the secondary prevention and therapeutic treatment of
RSV infections in adults demonstrating both large thera-
peutic window in vitro and safety in vivo. Nevertheless no
further development information has been reported re-
ally between 1991 and 19984,5,6
.
Although the research into the prevention and treatment
of RSV infection has been ongoing for almost 40 years,
vaccine development is difficult7,8 and to date there is no
clinically approved vaccine. Passive immunization with
the monoclonal antibody Palivizumab (Synagiss) has pro-
vided about 50% protection to high-risk children9. Ribavi-
rin, the only approved small molecule for treatment of
RSV, has to be given by a prolonged aerosol and there are
certain doubts as to its safety versus efficacy in treatment
of RSV infection. As such, the unmet medical need for
additional effective and safe treatments for RSV is para-
mount.
Fusion of the viral envelope or infected cell membranes
with uninfected cell membranes is an essential step in the
virus life cycle. The disruption of viral attachment and
entry to cells is a common strategy in the design of antivi-
ral therapies, as evidenced by successful approaches to
influenza and HIV inhibition10. In the case of the Pneu-
movirinae subfamily, which includes RSV, a distinctive
feature is the absence of hemagglutinin/neuraminidase
fusion proteins and the dependence on the F protein
cently19, 20
.
Figure 1, RSV fusion inhibitors under development.
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indazole, or isoxazole). Only imidazolepyridine analog 8a
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5
6
exhibited good potency presumably due to its nice fitting
the binding pocket. Inspired by the promising results,
some hydrophobic substitutions including methyl, fluoro,
trifluor, etc. were introduced to the R1 and R2 positions of
imidazole[1,2-a]pyridine core. The general synthesis of
these derivatives 8a-i is summarized in Scheme 1.
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3
7
8
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Scheme 1. The synthesis of 8a-i imidazopyrimide de-
rivatives
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(b)
(a)
9
10
11
(e)
(d)
(c)
13
7
14
12
BMS-433771(5) is an orally bioavailable and modestly po-
tent RSV inhibitor showing an EC50 of 24 nM over a range
of both laboratory and clinically relevant RSV strains2 .
1
(f )
(g)
BMS-433771 was progressed into pre-clinical evaluation22.
Although the above advantages endorsed BMS-433771 for
pre-clinical development, some potential concerns caught
our attention according to our internal assessment, in-
cluding modest activity, high in vivo clearance and short
T1/2 duration time (36 min), etc. Recognizing the areas for
improvement, our efforts were focused on the optimiza-
tion of potency and PK properties.
16
15
8 a-i
Reagents and conditions: (a) ethyl bromopyruvate, etha-
nol; (b) LiAlH4, THF, 0°C; (c) i) NBS, CH3CN, reflux; ii) SOCl-
2, DCM; (d) 1-cyclopropyl-1,3-dihydroimidazo[4,5-c] pyridin-
2-one(13), DMF, NaH; (e) 4-(TBDMSO)-butyne, CuI,
Pd(PPh3)2Cl2, Et3N, CH3CN, Microwave, 100°C; (f) TBAF/THF
0°C -rt; (g) Pd/C, H2, 3h 70-85%
BMS-433771 was speculated to bind in the hydrophobic
pocket created by the trimerization of the N-terminal
heptad repeats of the RSV F1 protein2 ,24. According to the
3
The synthesis of imidazole[1,2-a]pyridine analogue
8
commenced with commercially available 2-amino-
pyridine(9), which was cyclized with ethyl bromopyruvate
via heating in ethanol to generate the imidazole[1,2-
a]pyridine-2-ethyl ester 10, followed by reduction with
LAH, bromination, chlorination, and then alkylation with
the right part: 1-cyclopropyl-1,3-dihydroimidazo[4,5-c]
pyridin-2-one(13)23 to yield intermediate 3-bromo-
imidazole[1,2-a]pyridine 14. This intermediate was then
reported binding mode and the internal docking results
(Figure 1), there remains some space around the BMS-
433771 benzimidazole portion in the hydrophobic pocket
close to LYS191 and Val192, as well as the side chain part,
which is exposed to the surface of the pocket around
Asp194 and Leu195. This observation prompted us to ex-
plore both benzimidazole region and side chain in order
to improve potency and physicochemical properties.
subjected to
a
Sonogashira coupling with 4-(t-
butyldimethylsiloxy) butyne under microwave conditions.
After removal of TBDMS, the intermediate 16 was quickly
reduced with palladium on activated carbon to afford
imidazole[1,2-a]pyridine derivatives 8a-i in good yield
(70-80%).
Figure 2. The docking model of RSV fusion inhibition with
BMS-433771(right)16 and 8h(left).
Table 1. The antiviral activity of imidazole[1,2-a] pyri-
dine analogs 8a-j
Com-
R1
R2
EC50(µM)a CC50
pounds
(µM)a
A strain
5
-
-
0.028
0.217
>100
>100
>100
>100
8a
8b
8c
Me
F
H
H
H
0.096
0.422
Cl
Several bioisosteres of the benzimidazole were examined
to identify the optimal replacement (such as pyrazole,
2
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ACS Medicinal Chemistry Letters
logue 8d with an EC50 of 2.89 µM. Surprisingly, the sub-
8d
8e
8f
CF3
H
H
2.89
>100
>100
>100
>100
>100
>100
>100
1
2
3
4
5
6
7
8
9
10
stitutions at the 7-position (R2) can tolerate more broad
modification, and exhibited a trend toward potency im-
provement. Lastly, unprecedented single digital nanomo-
lar potency was obtained when methyl(8e), ethyl(8f) or
chloro(8j) were introduced as R2 of 8, these compounds
demonstrated 3-5 folds activity improvement in compari-
son to 5 with an EC50 below 10 nM and CC50 greater
than 100 µM. The introduction of 7-substitution chloro or
methyl had a significant impact on retaining potency.
These promising results encouraged us to further explore
the appropriate substitution pattern of shown in table 1.
Me
Et
F
0.006
0.007
0.023
0.017
0.217
0.007
H
8g
8h
8i
H
H
H
H
CF3
Cl
8j
H
a EC50: the concentration of test compound that protects
50% of infected cells, CC50: the concentration of drug that
manifests cytotoxicity towards 50% of uninfected HEp-2 cells
in the absence of virus. Values are means of two or more
experiments performed on consecutive weeks25.
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Table 2. The antiviral activity of imidazole[1,2-a] pyr-
idine analogs 8j-jr
The antiviral activity of these compounds was evaluated
by the reduction of the cytopathic effect(CPE) induced by
the Long (A) strain of virus replicating in HEp-2 human
lung epithelial carcinoma cells4 (Table 1). The introduc-
tion of fluoro at 6 position of 8b resulted in the reduction
of activity about 4-fold with an
8j-jr
EC50 of 96 nM in comparison to BMS-433771. It was
found that the substitutions at 6-position (R1) of imidaz-
olepyridine were very rigid and couldn’t tolerate imidaz-
olepyridine derivatives. Some of the results are presented
below. The 6- methyl and chloro analogs (8a and 8c) were
much less potent with an EC50 of 0.217 µM and 0.422 µM,
respectively. Replacing the chloro with trifluoro substitu-
According to the new insight of the distinct impact of 7-
substitution on potency improvement, a number of 7-
chloroimidazopyridine analogs 8ja-r bearing various side
chain were synthesized as shown in table 2 to identify
more potent compounds with favorite MDO properties.
Compounds
R3
EC50(µM)
CC50(µM)
8j
(CH2)4OH
0.007
3.06
>100
22.27
22.49
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
8ja
8jb
8jc
8jd
8je
8jf
H
CN
0.086
1.93
CH2OH
COOH
25.5
CONH(CH2)2OH
CONH(CH2)2SO2Me
CH=CHCOOH
(CH2)2COOH
(CH2)2CONH2
(CH2)2CONH(CH2)2OH
(CH2)2CONHSO2Me
(CH2)2SO2Me
(CH2)2SO2Et
2.23
0.082
0.207
0.053
0.005
0.010
0.046
0.006
0.003
0.041
0.072
0.083
0.683
0.089
8jg
8jh
8ji
8jj
8jk
8jl
8jm
8jn
8jo
8jp
8jq
8jr
NH-n-butyl
NH-cyclohexane
NH(CH2)2-morpholine
CH2NH(CH2)2OH
Ph (p-SO2Me)
tion at 6 position(R1) resulted in an nearly inactive ana-
The synthesis of 8jc-jf was described in the scheme 2 be-
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low, whereas the preparation of 8jg-jm followed the cou- 8jj is more soluble with up to 3-fold LYSA increase. The
1
2
3
4
5
6
7
8
pling and reduction steps in scheme 1 and condensation
step in scheme 2.
PAMPA value of 8ji is subtly increased, however 8jj has a
little lower one (Table 3). 8jl and 8jm appear equally sol-
uble as BMS compound 5, and much better permeable. All
five compounds significantly improved microsome stabili-
ties. These significant advantages suggested superior PK
properties with higher bioavailability and lower clearance
could be achieved for these several leading compounds
toward further development. More DMPK and in vivo
data will be reported in due course.
Scheme 2. Synthesis of 7-substituted imidazopyridine
derivatives
(b)
(a)
(c)
9
11a
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(d)
Table 3. Physicochemical and Metabolic Properties of
leading compounds
8jd
8jc-jf
Reagents and conditions: (a) POCl3, DMF, 70°C; (b) NaH,
DMF, 70°C; (c) NaClO2,tBuOH/THF; (d) HATU,
Et3N.
Compounds Solubility Permeability Microsome
CYPInhibition
3A4/2C9/2D6
LYSAa
PAMPAa
Clearance
It was speculated from the docking results
that the R3 position might be exposed to an
open surface area of the pocket, which could
be flexible. Various modifications in this re-
gion may be tolerable, although potential hy-
(µg/mL)
(10-6*cm/s)
Humanb/Mousec (IC50, μM)
(mL/min/kg)
5
39
2.2
16.3/82
11.5/80
0.0/ 9.1
13.5/59
2.9/47
2.5/35
27.5/>50/>50
NA
8j
20
541
87
107
59
46
3.1
drogen bond interaction between the terminal
8jh
8ji
0.30
2.5
>50/>50/>50
NA
hydroxyl with Lys191. Based on this model,
new analogs 8ja-r with a variety of terminal
groups at 3-position(R3) were investigated.
8jj
0.96
3.6
NA
Table 2 revealed that many 7-chloro deriva-
tives including 8jb, 8jf, 8jh-jp and 8jr were
very potent RSV inhibitors, with EC50 of below
100 nM. Interestingly, even without a side
8jl
>50/>50/>50
>50/>50/>50
8jm
2.6
4.6/62
a Values are means of two or more experiments performed on consecutive
weeks
chain, a cyano analog 8jb still exhibited prominent antivi-
ral activity compared to 8ja, although mild cytotoxicity
was observed. Hydroxylmethyl, carboxylic acid or amide
replacement at R3 led to remarkable activity loss (8jc, 8jd
and 8je). The antiviral potency of methyl sulfone analog
8jf still remained with an IC50 below 100nM. For 8jf, Acid
elongation derivatives 8jg and 8jh were not very potent.
In contrast, several 7-chloro derivatives 8ji, 8jj, 8jl, 8jm
containing amide and alkyl sulfonyl as terminal groups of
side chain demonstrated high antiviral acidity with single
digital nanomolar IC50s. The most potent compound 8jm
has an IC50 of 3 nM, which is around 9-fold more potent
than BMS-433771(5). A few substituted amino-linked ana-
logs like 8jn, 8jp exhibited some potency decline, 8jq had
much weak activity with an IC50 of 0.68 µM. Replacing the
hydroxyl butyl with more hinderous para-methyl sulfonyl
phenyl at R3 position resulted in more than 10-fold activi-
ty loss(0.089 µM).
b. Human: high (>15), medium(5-15), low(<5)
c. Mouse: high (>68), medium(23-68), low(<23)
In summary, a series of imidazolepyridine derivatives
were conceived and synthesized according to our docking
studies. It was found 7-substitution is crucial for potency
maintaining and improvement, several highly potent
compounds 8ji, 8jl, and 8jm were identified with single
digital nanomolar activities, of which the most potent
compound 8jm showed an IC50 of 3 nM with up to 9
folds activity improvement relative to 5, low to medium
microsome clearance, and no CYP inhibition. The promis-
ing profile of 8jm supported further optimization efforts
of this series, which will be reported in due course.
ASSOCIATED CONTENT
The physicochemical and metabolic properties of several
potent 7-chloroimidazole pyridine analogs and BMS com-
pound 5 were profiled below(Table 3). 8jh exhibited high-
ly enhanced solubility and metabolic stability, however its
activity and permeability were not optimal. The solubility
of the amide 8ji is slightly better than BMS compound 5;
Supporting Information. Biological assays, synthetic pro-
cedures and analytical data for selected compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
4
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Timmerman, P.; Wuyts, K.; van Remoortere, P.; Janssens, F.; Wig-
AUTHOR INFORMATION
erinck, P.; Andries, K. Selection of a respiratory syncytial virus fu-
sion inhibitor clinical candidate. 2. Discovery of a morpholinoprop-
ylaminobenzimidazole derivative (TMC353121). J. Med. Chem.
2008, 51(4), 875-896
1
2
3
Corresponding Authors
* Tel: +86 21 3895 4910. E-mail: andrew.feng@roche.com
4
5
6
7
17. Mackman, R. L.; Sangi, M. ; Sperandio, D.; Parrish, J. P.; Eisenberg,
E., Perron, M., et al. Discovery of an Oral Respiratory Syncytial Vi-
rus (RSV) Fusion Inhibitor (GS-5806) and Clinical Proof of Concept
in a Human RSV Challenge Study. J. med. Chem. 2015. Just Ac-
cepted Manuscript.
Notes
The authors declare no competing financial interest.
ABBREVIATIONS
18. Douglas, J.L.; Panis, M.L.; Ho, E.; Lin, K.Y.; Krawczyk, S.H.;
Grant, D.M.; Cai, R.; Swaminathan, S.; Cihlar, T. Inhibition of res-
piratory syncytial virus fusion by the small molecule VP-14637 via
specific interactions with F protein. J. Virol. 2003, 77, 5054–5064
19. Razinkov, V.; Gazumyan, A.; Nikitenko, A.; Ellestad, G.; Krishna-
murthy, G. RFI-641 inhibits entry of respiratory syncytial virus via
interactions with fusion protein. Chem. Biol. 2001, 8, 645–659.
20. Morton, C.J.; Cameron, R.; Lawrence, L.J.; Lin, B.; Lowe, M.; Lut-
tick, A.; Mason, A.; Kimm-Breschkin, J.; Parker, M.W.; Ryan, J.; et
al. Structural characterization of respiratory syncytial virus fusion
inhibitor escape mutants: homology model of the F protein and a
syncytium formation assay. Virology, 2003, 311, 275–288
21. Yu, K. L.; Sin, N.; Civiello, R. L.; Wang, X. A.; Combrink, K. D.;
Gulgeze, H. B.; et al. Respiratory syncytial virus fusion inhibitors.
Part 4: Optimization for oral bioavailability. Bioorg. & med. Chem.
Let. 2007, 17(4), 895-901.
22. Cianci, C.; Meanwell, N.; Krystal, M. Antiviral activity and molecu-
lar mechanism of an orally active respiratory syncytial virus fusion
inhibitor. J. Antimicrob. Chemother. 2005, 55, 289–292.
23. Cianci, C.; Langley, D.R.; Dischino, D.D.; Sun, Y.X.; Yu, K.L.;
Stanley, A.; Roach, J.; Li, Z.F.; Dalterio, R.; Colonno, R.; et al. Tar-
geting a binding pocket within the trimer-of-hairpins: Small-
molecule inhibition of viral fusion. Proc. Natl. Acad. Sci. 2004, 101,
15046–15051.
8
9
RSV, Respiratory Syncytial Virus; LYSA, lyophilization solu-
bility assay; PAMPA, partial permeability assay; MDO, multi-
ple dimensional optimization; CYP, Cytochrome P450 en-
zymes.
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Discovery of Imidazopyridine Derivatives as Highly Potent Respira-
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†
Song Feng* , Di Hong†, Baoxia Wang†, Xiufang Zheng†, Kun Miao†, Lisha Wang‡, Hongying
Yun†, Lu Gao§, Shuhai Zhao†, Hong C. Shen†
†
‡
§
Medicinal Chemistry, Molecular Design and Chemical Biology, Infectious Diseases, Pharmaceutical Research
and Early Development, Roche Innovation Center Shanghai, Building 5, Lane 720, Cai Lun Road, Shanghai 201203,
China
RSVLong strain:
EC /CC : 3.0 (nM) / >100 ( M)
µ
50
50
LYSA: 46.0 (ꢀg/mL)
PAMPA: 2.64 (10ꢁ6* cm/s)
HLM: 4.64 (mL/min/kg)
CYPinhibiton:
3A4/2C9/2D6: >50/> 50/>50 (uM)
BMS433771
(5)
8 jm
6
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