MK-8325: A silyl proline-containing NS5A inhibitor with pan-genotype activity for treatment of HCV

Article abstract of DOI:10.1016/j.bmcl.2018.03.049

HCV NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive components for inclusion in an all oral fixed dose combination regimen. Herein, we describe the discovery and characterization of silyl proline-containing HCV NS5A inhibitor MK-8325 with good pan-genotype activity and acceptable pharmacokinetic properties.

Full text of DOI:10.1016/j.bmcl.2018.03.049

Accepted Manuscript
MK-8325: A Silyl Proline-Containing NS5A Inhibitor with Pan-Genotype Ac-
tivity for Treatment of HCV
Anilkumar G. Nair, Qingbei Zeng, Oleg Selyutin, Stuart B. Rosenblum,
Yueheng Jiang, De-Yi Yang, Kerry Keertikar, Guowei Zhou, Michael Dwyer,
Seong Heon Kim, Bandarpalle Shankar, Wensheng Yu, Ling Tong, Lei Chen,
Robert Mazzola, John Caldwell, Haiqun Tang, Sony Agrawal, Rong Liu, Rong
Kong, Paul Ingravallo, Ellen Xia, Ying Zhai, Amin Nomeir, Ernest Asante-
Appiah, Joseph A. Kozlowski
PII:
S0960-894X(18)30242-7
https://doi.org/10.1016/j.bmcl.2018.03.049
BMCL 25703
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 January 2018
17 March 2018
19 March 2018
Please cite this article as: Nair, A.G., Zeng, Q., Selyutin, O., Rosenblum, S.B., Jiang, Y., Yang, D-Y., Keertikar,
K., Zhou, G., Dwyer, M., Kim, S.H., Shankar, B., Yu, W., Tong, L., Chen, L., Mazzola, R., Caldwell, J., Tang, H.,
Agrawal, S., Liu, R., Kong, R., Ingravallo, P., Xia, E., Zhai, Y., Nomeir, A., Asante-Appiah, E., Kozlowski, J.A.,
MK-8325: A Silyl Proline-Containing NS5A Inhibitor with Pan-Genotype Activity for Treatment of HCV,
Bioorganic & Medicinal Chemistry Letters (2018), doi: https://doi.org/10.1016/j.bmcl.2018.03.049
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

MK-8325: A Silyl Proline-Containing NS5A Inhibitor with Pan-Genotype
Activity for Treatment of HCV
Anilkumar G. Nair,* Qingbei Zeng, Oleg Selyutin, Stuart B. Rosenblum, Yueheng
Jiang, De-Yi Yang, Kerry Keertikar, Guowei Zhou, Michael Dwyer, Seong Heon Kim,
Bandarpalle Shankar, Wensheng Yu, Ling Tong, Lei Chen, Robert Mazzola, John
Caldwell, Haiqun Tang, Sony Agrawal, Rong Liu, Rong Kong, Paul Ingravallo, Ellen
Xia, Ying Zhai, Amin Nomeir, Ernest Asante-Appiah, Joseph A. Kozlowski
Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
This is where the receipt/accepted dates will go; Received Month XX, 2018; Accepted Month XX, 2018 [BMCL RECEIPT]
Abstract— HCV NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive
components for inclusion in an all oral fixed dose combination regimen. Herein, we describe the discovery and characterization of silyl
proline-containing HCV NS5A inhibitor MK-8325 with good pan-genotype activity and acceptable pharmacokinetic properties.
[BMCL ABSTRACT] ©2000 Elsevier Science Ltd. All rights reserved.
Given the medical need for improved outcomes for
genotype 1 patients, as well as those infected with other
genotypes, efforts toward improved HCV treatment
options continued. Current therapies for HCV infection
combine two or more oral direct-acting antiviral agents
(DAAs). These regimens target the NS3/4A protease,
the NS5A phosphoprotein or the NS5B polymerase.
The approved combination drugs include Harvoni,
Technivie, Zepatier, Epclusa and Mavyret.4
Hepatitis C virus (HCV) is currently the leading cause
of chronic liver disease and liver transplantation, and
has become the most common blood-borne infection in
developed countries with approximately 71 million
people infected globally.1 The early standard of care for
HCV involved pegylated interferon- (IFN) and
ribavirin (RBV). The year-long treatment was
accompanied by significant side effects and limited
efficacy. Individuals who managed to complete the
treatment, and were infected with the most common
virus, genotype 1, had response rates of less than 50%.2
Improved sustained virologic response (SVR) outcomes
became possible by combining IFN and RBV with
protease inhibitors (PI) such as boceprevir (Victrelis)
and telaprevir (Incivek).3 However, many patients still
did not obtain SVR leaving room for improvement of
outcomes.
Despite gaps in the understanding of the role of the
NS5A protein in the virus replication cycle, inhibitors of
NS5A continue to be a component in the combination
drugs. While its exact role in viral replication remains
unclear, the NS5A protein is known to play an integral
role in viral replication and release of virus particles.5
NS5A also interacts with cellular proteins and host
factors required for HCV replication as well as being
important for interference with the host intracellular
immune response; the NS5A protein therefore is a target

of high interest.6 We have had a continued interest in the
identification and development of potent NS5A
inhibitors as part of an all-oral regimen.7-8 As indicated
above, HCV NS5A has been clinically validated with
approved HCV compounds including daclatasvir,9
ledipasvir,10 ombitasvir,11 elbasvir7 and velpatasvir.12 In
a previous letter,13 we described the discovery of silyl
proline-containing HCV NS5A inhibitors with
improved pan genotype activity, and their rat PK
profiles, when compared to MK-48827 (Figure 1).
During this SAR exploration we made extensive
variations in the central core, proline and valine cap
regions of the initial leads. Two inhibitor structures 1
and 2 derived from this investigation consist of a
naphthylimidazole-phenyl central core with silaproline
and difluoro substituted proline on either side. We were
curious if the introduction of silicon to these molecules
would lead to any improvements or deficiencies in their
properties. We now describe the details of the
characterization.
afforded the pinacolboronate intermediate 9. Synthesis
of 1 was accomplished by palladium catalyzed coupling
of aryl bromide 6 and pinacolboronate 9, followed by
double cleavage of Boc-protecting groups under acidic
conditions and double amidation to introduce the MOC-
valine fragments (Scheme 1). A similar synthetic
approach was used for the synthesis of compound 2 in
which the positions of silyl proline and difluoro
substituted proline are reversed (Scheme 2).15
Scheme 1. Synthesis of 1, Reagents: (a) HATU, DIPEA, THF, 0°C; (b)
AcOH, 60°C; (c) 4-Br-PhCOCH2Br; DIPEA, DMF; (d) NH4OAc,
Xylene, 1h, 130°C; (e) Bis(pinacolato)diboron, Pd(Ph3)4, KOAc, 80°C;
(f) Pd(dppf)Cl2.CH2Cl2, Na2CO3, 90°C; (g) HCl; (h) (S)-N-Moc-Val,
HATU, DIPEA, DMF, -50°C-10°C .
Figure 1. SAR development to silyl proline containing lead molecules
Scheme 1 illustrates the general synthesis of 1. The
desired Boc protected silaproline starting material 3 was
synthesized as described previously.13-14This under
HATU
mediated
coupling
with
diamino
bromonaphthalene derivative 4 provided the amide
intermediate 5 as the major isolated product, which is
sterically more favored regioisomer. Intermediate 5 by
heating with acetic acid underwent ring closure yielding
the bromo naphthylimidazole intermediate 6.
Simultaneously, treatment of Boc-protected (S)-difluoro
Scheme 2. Synthesis of 2, retrosynthetic approach
The lead compounds 1 and 2 were highly potent against
most HCV genotypes tested with EC50 values in the
sub-nM range (Table 1). Their potencies against GT2b,
encoding the M31 variant, are reduced.
substituted
proline
7
with
2-bromo-1-(4-
bromophenyl)ethan-1-one afforded ester intermediate 8.
This under heating with ammonium acetate and
subsequent treatment with bis(pinacolato)diboron

well as species differences. Compound 2 showed a
minor risk for human induction and was followed up in
RIS study to evaluate the risk for induction in humans.
It showed a low potential of induction in the study
(Table 4). Both compounds displayed similar off-target
profiles. Compound 1, subsequently renamed MK-
8325, was selected for further characterization, as it was
comparable overall to compound 2 but lacked the initial
mRNA signal in human hepatocytes.
Table 1. In-vitro GT-WT potency profile in comparison to MK-4882
Replicon EC50 (nM)
Genotype (WT)
GT1a
MK-4882
0.01
0.001
0.4
Compd 1
0.015
0.001
0.003
125
Compd 2
0.009
0.001
0.002
77
GT1b
GT2a
GT2b
286
4
0.25
GT3a
0.2
0.3
0.05
GT4a
0.02
Table 4. Enzyme inhibition/ induction profile in comparison to MK-4882
Both compounds also demonstrated potencies
comparable to MK-4882 against a panel of mutants in
both the GT1a and GT1b backgrounds (Table 2).
Interestingly, they showed improved activity against the
more common GT1b variants.
Tox parameter
CYP Inhibition
MK-4882
Compd 1
Compd 2
> 20 µM
> 20 µM
> 20 µM
> 20 µM
> 20 µM
> 20 µM
3A4
2C9
2D6
> 20 µM
> 20 µM
> 20 µM
CYP Induction
Table 2. In-vitro GT-mutant potency profile in comparison to MK-4882
3 µM
-
> 10 µM
0.2(rel Rif)
>3 µM
-
PXR
Replicon EC50 (nM)
0.31(rel Rif)
0.3 µM
Hu Hep mRNA3A4
GT (Mutant)
1a M28V
1a Q30H
1a Q30R
1a L31V
1a Y93C
1aY93H
MK-4882
0.004
5.5
Compd 1
0.1
Compd 2
0.09
2
6
9
2
47
0.02
0.01
4
8.5
6.4
8.8
20
0.5
2.3
18
18
2
49
0.03
0.02
MK-8325 demonstrates no cell toxicity with a CC50
>
25 µM against Huh-7 replicon cells in a standard MTS
assay. This level is improved compared to MK-4882 (7
µM). This yields a therapeutic index for MK-8325 of >
8x106 as measured against the EC50 value for GT1b.
1b L31V
1b Y93H
Compounds 1 and 2 showed better overall PK profiles,
across species, compared to MK-4882 (Table 3).
MK-8325 has many attractive drug metabolism
attributes and pharmacokinetics suitable for once-daily
dosing which are summarized below (Table 5). The
compound is orally absorbed from the GI tracts of rats,
dogs, and cynomolgus monkeys with low to moderate
Table 3. Pharmacokinetics data in comparison to MK-4882
PK Parameter
Rat
MK-4882
Compd 1
Compd 2
9.3
2
1.7
(2)
5.6
7.6
5
CL(mL/min/kg)
T½ (h)
PO AUC(µM.h/mL)
(dose, mpk)
C24h (nM)
%F
7
10
9
(5)
94
64
bioavailability.
The
limited
absorption
and
bioavailability is due to low passive permeability and
low solubility as the IV clearance is relatively low in all
species studied. The compound showed high protein
binding in all species (>99.9%) and is highly distributed
to the target organ (liver/plasma ratio = 27X) with
minimal or no brain distribution (brain/plasma ratio =
0.04). In rats, the compound-derived radioactivity is
excreted in urine, bile and feces after IV administration.
Approximately 27% of the IV dose was excreted as
unchanged compound in urine, bile and feces in rats,
while the metabolic pathways are oxidative. MK-8325
is neither an inhibitor nor an inducer of human major
CYPs, therefore potential DDI with CYP substrates as a
(5)
4
38
51
28
Dog
6.4
4.7
1.1
(1)
0.8
18
4.2
(2)
CL(mL/min/kg)
T½ (h)
PO AUC(µM.h/mL)
(dose, mpk)
C24h (nM)
%F
0.7
30
32
(2)
0.4
47
4
26
40
9(fasted)
Monkey
9.1
3
nd
1.2
17
4
CL(mL/min/kg)
T½ (h)
PO AUC(µM.h/mL)
(dose, mpk)
C24h (nM)
%F
0.7
15
26
(2)
273
45
(2)
perpetrator is unlikely.
The compound was not
nd
nd
55
12
metabolized by hepatocytes or liver microsomes of any
species including humans; therefore, reaction
phenotyping could not be assessed. However, given that
the compound is excreted unchanged in both rats and
dogs suggesting multiple elimination pathways, the
potential for DDI as a victim of CYP inhibitors or
inducers is low. MK-8325 has been shown to be a
substrate for human OATP1B3 and may be a substrate
for human OATP1B1, suggesting that potent inhibitor
As one of the observations with MK-4882 was PXR
induction, and both compounds were examined in
assays for that activity. The potential of an HCV
inhibitor to act as a perpetrator/victim16 is difficult to
assess a priori given the complicated transporter effects
across compartments and the variable concentration in
the liver versus what can be measured in the plasma, as

or inducers of these transporters may affect its uptake
into the liver and could result in DDI. MK-8325
partially inhibited human OATP1B1, but modeling
using projected portal plasma concentrations at the
loading dose, suggested that the potential to cause DDI
with substrates of OATP1B1 is low.
Table 5. Mean± SD of Pharmacokinetic Parameters in Rats, Dogs, and
Monkeys of MK-8325
However, when the compound was administered by
infusion into the portal vein (1 or 5 hr) at 5 mg/kg as a
solution in the NMG vehicle, the bioavailability
increased to ~100% with a higher AUC observed after
the 1-hr infusion (32 vs 23 µM.hr) indicating that the GI
tract is the barrier for bioavailability.
MK-8325 exhibited minimal inhibition on hERG
current up to the maximum tested concentration of 30
µM. Similarly, a minimal effect on ICaL and no effect on
IKs and INa at 30 µM was observed. No major alerts were
noted in a broad counter screen panel (Pan Labs). It was
tested for mutagenicity in a 5-strain exploratory
microbial mutagenesis (Ames) and was negative.
MK-8325 was evaluated in an exploratory 4-day oral
lead optimization study in female rates at doses up to 30
mg/kg/day. This corresponds to projected exposure
multiples of ~27-35X [AUC] and 26-29X [Cmax].
Exposure multiples are based on projected human
values of 1.0-1.3 uM.hr for AUC and 72-82 nM for
Cmax which encompass both loading and maintenance
doses. The NOAEL for this study is >30mg/kg/day.
This was further evaluated in an exploratory 7-day oral
tolerability study in male rats (oral, 0.5%
methylcellulose), at doses up to 750 mg/kg/day, which
showed dose dependent increases in drug exposure
multiples with findings limited to slight increases in
monocytes at 100 mg/kg/day and 750 mg/kg/day. There
was no mortality observed. Further toxicity studies in
dogs at doses up to 750 mg/kg/day also demonstrated
the compound is safe.
In summary, compound 1 (MK-8325) is an HCV NS5A
inhibitor with excellent replicon activity across multiple
genotypes. As we reported earlier, the silicon analogs
also showed an improved PK profile in rat compared to
the carbon analogs.13 The human dose prediction using
allometric scaling from rat, dog and monkey studies
(corrected with PPB) based on maintaining a trough free
plasma concentration of 1XEC90 showed a projected
mean loading dose of 60 mg/day. In vitro and in vivo
assays showed MK-8325 to be orally bioavailable with
pharmacokinetics suitable for once-daily dosing in
patients and good overall ADME profiles.
Rat
Dog
Monkey
(1/2 mpk,
IV/PO)
1.2 ± 0.3
1.7 ± 0.14
17 ± 3.0
20 ± 3.0
0.18 ± 0.1
PK Parameter
(2.5/5 mpk, (1/2 mpk,
IV/PO)
5.6 ± 0.4
3.7 ± 0.6
7.6 ± 1.0
9.7 ± 2.0
0.33 ± 0.04
IV/PO)
0.8 ± 0.1
1.3 ± 0.2
18 ± 2.0
26 ± 2.0
IV CL(mL/min/kg)
IV Vdss (L/kg)
IV t1/2 effective (hr)
IV t1/2 terminal (hr)
0.27 ±
0.1
PO Cmax (µM)
5.3 ± 1.0
5.0 ± 1.0
1.0 ± 0.2
2.7 ± 1.0
4.2 ± 2.0
2.1 ± 1.0
Tmax (hr)
4.7 ± 1.0
4.0 ± 1.0
2.0 ± 0.5
PO AUC(µM.h)
PO AUC(0- / dose
(µM.h)/(mg/kg)
)
28 ± 6.0
8.7 ± 3.6
Bioavailability (%)
11.7 ± 3.0
MK-8325 (Compd 1) as a dihydrochloride salt was
administered IV as a solution in 20% hydroxypropyl- β-
cyclodextrin (20% HPβCD) or PO as a suspension in
0.4% hydroxylpropyl methylcellulose (HPMC) to male
SD rats, male beagle dogs and male cynomolgus
monkeys at the doses specified in Table 3. Dogs were
subjected to overnight fast while rats and monkeys were
not fasted. Plasma samples were collected at intervals
for the analysis of parent compound by non-validated
LC-MS/MS assays. The pharmacokinetic parameters
were calculated using non-compartmental analysis. The
IV clearance was low and corresponded to
approximately 3-7% of hepatic blood flow in all species
evaluated. The Vdss was moderate and the effective t1/2
was long which would be consistent with QD dosing in
humans. The terminal t1/2 was somewhat longer than the
effective t1/2 suggesting rate-limited return from tissue
compartments. Even though the bioavailability was low
to moderate (9-28%), the dose normalized oral AUC
ranged from 1-2 µM.hr/mg/kg, indicating good oral
exposure. The low to moderate bioavailability is likely
due to limited absorption and low solubility as the IV
clearance is relatively low. This is also consistent with
the low permeability in MDCKII cells (0.8 X10-6 cm/s,
8 nm/s). MK-8325 is a basic compound with pKa’s of
3.57 and 5.69. This compound shows a pH dependent
solubility profile, and has high solubility under acidic
conditions (aqueous solubility is 0.065 mg/mL@ pH
3.1) and modest solubility at neutral conditions (0.0027
mg/mL@ pH 7.3).
References and notes
1. WHO Hepatitis fact sheet Updated October 2017.
2. Bobeck, D. R.; Schinazi, R. F.; Coats, S. J. Antivir.
Ther. 2010, 15, 935.
3. Sheridan, C. Nat. Biotechnol. 2011, 29, 553.
4. a). Gilead Sciences Inc. 2015. Harvoni TM
(ledispasvir and Sofosbuvir) tablets, for oral use.
Prescribing information. Gilead Sciences Inc. Foster
City, CA.; b). AbbVie Inc. 2015. Technivie TM
(ombitasvir/paritaprevir/ritonavir), copackaged for
oral use. Initial US approval. AbbVie, Inc. North
Chicago, IL.; c) Merck and Co. Inc. 2016. Zepatier
In an attempt to enhance the oral bioavailability, the
compound was administered as a solution in a vehicle
consisting of 10% N-methyl-2-pyrrolidone/50%
propylene glycol/40% polyethylene glycol 300 (NMG
vehicle). There was no improvement in bioavailability.
TM
(Elbasvir and grazoprevir) tablets. Initial US

approval. Merck and Co, Kenilworth, NJ.; d) Gilead
Sciences Inc. 2016. Epclusa TM (velpatasvir and
Sofosbuvir) tablets, for oral use. Prescribing
Henry, L.; Hunt, S. J. Hepatol. 2016, 65, 33.
13. Nair, A. G.; Zeng, Q.; Selyutin, O.; Rosenblum, S.
B.; Jiang, Y.; Yang, D-Y.; Keertikar, K.; Zhou, G.;
Dwyer, M. P.; Kim, S. H.; Shankar, B.; Yu, W.;
Tong, L.; Chen, L.; Mazzola, R.; Caldwell, J.; Tang,
H.; Allard, M. L.; Buckle, R. N.; Gauuan, P. J. F.;
Holst, C. L.; Martin, G.S.; Naicker, K. P.;
Vellekoop, S.; Agrawal, S.; Liu, R.; Kong, R.;
Ingravallo, P.; Xia, E.; Zhai, Y.; Nomeir, A.;
Kozlowski, J. A. Bioorg. Med. Chem. Lett., 2016,
26(5), 1475.
14. Vivet, B.; Cavelier, F.; Martinez, J. Eur. J. Org.
Chem. 2000, 807.
15. Refer to patent application WO2011/112429 for
detailed procedures and schemes.
16. Mogalian, E.; German, P.; Kearney, B. P.; Yang, C.
Y.; Brainard, D.; McNally, J.; Moorehead, L.;
Mathias, A.; Clin Pharmacokinet. 2016, 55, 605.
information. Gilead Sciences Inc. Foster City, CA.;
e) AbbVie Inc. 2017. Mavyret TM
(glecaprevir/pibrentasvir), tablets for oral use. Initial
US approval. AbbVie, Inc. North Chicago, IL
5. McGivern, D. R.; Masaki, T.; Williford, S.;
Ingravallo, P.; Feng, Z.; Lahser, F.; Asante-Appiah,
E.; Neddermann, P.; Francesco, R. D.; Howe, A. T.;
Lemon, S. M. Gastroenterology 2014, 147, 453.
6. a) Schinazi, R. F.; Bassit, L.; Gavegnano, C. J. Viral
Hepat. 2010, 17, 77.; b) Katze, M. G.;
Kwieciszewski, B.; Goodlett, D. R.; Blakely, C. M.;
Neddermann, P.; Tan, S. L.; Aebersold, R. Virology
2000, 278, 501.; c) Kim, J.; Lee, D.; Choe, J.
Biochem. Biophys. Res. Commun. 1999, 257, 777.
7. Coburn, C. A.; Meinke, P. T.; Chang, W.; Fandozzi,
C. A.; Graham, D. J.; Hu, B.; Huang, Q.; Kargman,
S.; Kozlowski, J.; Liu, R.; McCauley, J. A.; Nomeir,
A. A.; Soll, R. M.; Vacca, J. P.; Wang, D.; Wu, H.;
Zhong, B.; Olsen, D. B.; Ludmerer, S. W.
ChemMedChem 2013, 8, 1930.
8. Tong, L.; Yu, W.; Chen, L.; Selyutin, O.; Dwyer,
M. P.; Nair, A. G.; Mazzola, R.; Kim, J-H.; Sha, D.;
Yin, J.; Ruck, R. T.; Davies, I. W.; Hu, B.; Zhong,
B.; Hao, J.; Ji, T.; Zan, S.; Liu, R.; Agrawal, S.; Xia,
E.; Curry, S.; McMonagle, P.; Bystol, K.; Lahser,
F.; Carr, D.; Rokosz, L.; Ingravallo, P.; Chen, S.;
Feng, K-I.; Cartwright, M.; Asante-Appiah, E.;
Kozlowski, J. A. J. Med. Chem. 2017, 60(1), 290.
and references cited therein.
9. a) Gao, M.; Nettles, R. E.; Belema, M.; Snyder, L.
B.; Nguyen, V. N.; Fridell, R. A.; Serrano-Wu, M.
H.; Langley, D. R.; Sun, J.-H.; O’Boyle, D. R.;
Lemm, J. A.; Wang, C.; Knipe, J. O.; Chien, C.;
Colonno, R. J.; Grasela, D. M.; Meanwell, N. A.;
Hamann, L. G. Nature 2010, 465, 96; b) Nettles, R.
E.; Gao, M.; Bifano, M.; Chung, E.; Persson, A.;
Marbury, T. C.; Goldwater, R.; DeMicco, M. P.;
Rodriguez-Torres, M.; Vutikullird, A.; Fuentes, E.;
Lawitz, E.; Lopez-Talavera, J. C.; Grasela, D. M.
Hepatology 2011, 54, 1956.; c) Belema, M.;
Nguyen, V.; Bachand, C.; Deon, D.; Goodrich, J.;
James, C.; Lavoie, R.; Lopez, O.; Martel, A.;
Romine, J.; et al. J. Med.Chem. 2014, 57, 2013.
10. a) Link, J. O.; Taylor, J. G.; Xu, L.; Mitchel, M.;
Guo, H.; Liu, H.; Kato, D.; Kirschberg, T.; Sun, J.;
Squires, N.; Parrish, J.; Keller, T.; Yang, Z.; Yang,
C.; Matles, M.; Wang, Y.; Wang, K.; Cheng, G.;
Tian, Y.; Mogalian, E.; Mondou, E.; Cornprost, M.;
Perry, J.; Desai, M. C. J. Med. Chem. 2014, 57(5),
2033.
11. DeGoey, D.; Randolph, J.; Liu, D.; Pratt, J.;
Hutchins, C.; Donner, P.; Krueger, A.; Matulenko,
M.; Patel, S.; Motter, C.; et al. J. Med. Chem. 2014,
57, 2047.
12. Younossi, Z. M.; Stepanova, M.; Feld, J.; Zeuzem,
S.; Jacobson, I.; Agarwal, K.; Hezode, C.; Nader, F.;

MK-8325: A Silyl Proline-Containing NS5A
Inhibitor with Pan-Genotype Activity for
Treatment of HCV
Anilkumar G. Nair,* Qingbei Zeng, Oleg Selyutin, Stuart B.
Rosenblum, Yueheng Jiang, De-Yi Yang, Kerry Keertikar,
Guowei Zhou, Michael P. Dwyer, Seong Heon Kim, Bandarpalle
Shankar, Wensheng Yu, Ling Tong, Lei Chen, Robert Mazzola,
John Caldwell, Haiqun Tang, Melissa L. Allard, Ronald N.
Buckle, Polivina Jolicia F. Gauuan, Christian L. Holst, Gregory
S. Martin, Kannan P. Naicker, Samuel Vellekoop, Sony Agrawal,
Rong Liu, Rong Kong, Paul Ingravallo, Ellen Xia, Ying Zhai,
Amin Nomeir, Ernest Asante-Appiah, Joseph A. Kozlowski
HCV NS5A inhibitors have shown impressive in vitro potency
profiles in HCV replicon assays thus making them attractive
components for inclusion in an all oral fixed dose combination
regimen. Herein, we describe the discovery and characterization
of silyl proline-containing HCV NS5A inhibitor MK-8325 with
pan-genotype activity and acceptable pharmacokinetic properties.