P2-quinazolinones and bis-macrocycles as new templates for next-generation hepatitis C virus NS3/4a protease inhibitors: Discovery of MK-2748 and MK-6325

Article abstract of DOI:10.1002/cmdc.201402558

With the goal of identifying inhibitors of hepatitis C virus (HCV) NS3/4a protease that are potent against a wide range of genotypes and clinically relevant mutant viruses, several subseries of macrocycles were investigated based on observations made during the discovery of MK-5172. Quinazolinone-containing macrocycles were identified as promising leads, and optimization for superior cross-genotype and mutant enzyme potency as well as rat liver and plasma concentrations following oral dosing, led to the development of MK-2748. Additional investigation of a series of bis-macrocycles containing a fused 18- and 15-membered ring system were also optimized for the same properties, leading to the discovery of MK-6325. Both compounds display the broad genotype and mutant potency necessary for clinical development as next-generation HCV NS3/4a protease inhibitors.

Full text of DOI:10.1002/cmdc.201402558

DOI: 10.1002/cmdc.201402558
Full Papers
P2-Quinazolinones and Bis-Macrocycles as New Templates
for Next-Generation Hepatitis C Virus NS3/4a Protease
Inhibitors: Discovery of MK-2748 and MK-6325
Michael T. Rudd,*[a] John W. Butcher,[a] Kevin T. Nguyen,[a] Charles J. McIntyre,[a]
Joseph J. Romano,[a] Kevin F. Gilbert,[a] Kimberly J. Bush,[a] Nigel J. Liverton,[a] M.
Katharine Holloway,[b] Steven Harper,[c] Marco Ferrara,[c] Marcello DiFilippo,[c]
Vincenzo Summa,[c] John Swestock,[d] Jeff Fritzen,[d] Steven S. Carroll,[e] Christine Burlein,[e]
Jillian M. DiMuzio,[e] Adam Gates,[e] Donald J. Graham,[e] Qian Huang,[e] Stephanie McClain,[e]
Carolyn McHale,[e] Mark W. Stahlhut,[e] Stuart Black,[f] Robert Chase,[f] Aileen Soriano,[f]
Christine M. Fandozzi,[g] Anne Taylor,[g] Nicole Trainor,[g] David B. Olsen,[e] Paul J. Coleman,[a]
Steven W. Ludmerer,[e] and John A. McCauley*[a]
With the goal of identifying inhibitors of hepatitis C virus (HCV)
NS3/4a protease that are potent against a wide range of geno-
types and clinically relevant mutant viruses, several subseries
of macrocycles were investigated based on observations made
during the discovery of MK-5172. Quinazolinone-containing
macrocycles were identified as promising leads, and optimiza-
tion for superior cross-genotype and mutant enzyme potency
as well as rat liver and plasma concentrations following oral
dosing, led to the development of MK-2748. Additional investi-
gation of a series of bis-macrocycles containing a fused 18-
and 15-membered ring system were also optimized for the
same properties, leading to the discovery of MK-6325. Both
compounds display the broad genotype and mutant potency
necessary for clinical development as next-generation HCV
NS3/4a protease inhibitors.
Introduction
The leading indication for liver transplantation,[1] hepatitis C is
a chronic infection caused by the hepatitis C virus (HCV), which
replicates primarily in the liver and is estimated to affect ap-
proximately 3% of the world’s population with 3–4 million
new infections per year.[2] Six major genotypes (gt) of HCV
have been identified, with gt1, gt2, and gt3 representing more
than 90% of the infections in the developed world. Within
genotypes, the virus also displays a high degree of genetic
heterogeneity. Although HCV has been treated since the late
1990s[3] with a regimen of co-dosed PEGylated interferon-
a (IFN-a) and ribavirin[4] that lasts for up to one year, severe
side effects[5] and moderate efficacy have limited the utility of
this treatment. Efforts to improve this regimen include devel-
opment of direct antivirals that inhibit key steps in the viral
replication process, and significant progress has been made on
this front over the past several years.[6] One major focus of re-
search has been the inhibition of HCV NS3/4a protease,[7,8]
a serine protease critical for viral replication. Clinical proof-of-
concept was initially established by researchers at Boehringer
Ingelheim with BILN-2061.[9] Subsequently, Vertex (VX-950, te-
laprevir[10]), Merck (SCH-503034, boceprevir;[11] MK-7009, vani-
previr[12–14]) and Johnson & Jonson (simeprevir[15]) have gained
[a] Dr. M. T. Rudd, J. W. Butcher, K. T. Nguyen, C. J. McIntyre, J. J. Romano,
K. F. Gilbert, K. J. Bush, Dr. N. J. Liverton, Dr. P. J. Coleman,
Dr. J. A. McCauley
[e] Dr. S. S. Carroll, C. Burlein, J. M. DiMuzio, A. Gates, D. J. Graham, Q. Huang,
S. McClain, C. McHale, M. W. Stahlhut, Dr. D. B. Olsen, Dr. S. W. Ludmerer
Department of Antiviral Research
Department of Medicinal Chemistry
Merck Research Laboratories, West Point, PA (USA)
Merck Research Laboratories, West Point, PA (USA)
E-mail: michael_rudd@merck.com
[f] S. Black, R. Chase, A. Soriano
Department of Antiviral Research
Merck Research Laboratories, Kenilworth, NJ (USA)
john_mccauley@merck.com
[b] Dr. M. K. Holloway
[g] Dr. C. M. Fandozzi, A. Taylor, N. Trainor
Department of Drug Metabolism
Department of Chemistry, Modeling and Informatics
Merck Research Laboratories, West Point, PA (USA)
Merck Research Laboratories, West Point, PA (USA)
[c] Dr. S. Harper, Dr. M. Ferrara, Dr. M. DiFilippo, Dr. V. Summa
Department of Medicinal Chemistry
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cmdc.201402558.
Merck Research Laboratories, Rome (Italy)
[d] J. Swestock, J. Fritzen
Department of Discovery Process Chemistry
Merck Research Laboratories, West Point, PA (USA)
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regulatory approval for HCV NS3/4a inhibitors that are dosed
in combination with IFN and ribavirin; these lead to improve-
ments in sustained virological response (SVR) rates. Several
other antiviral mechanisms have also been aggressively pur-
sued, and Gilead recently obtained approval for an NS5B poly-
merase inhibitor (sofusbuvir[16]), which is a key component of
the currently recommended treatment for many genotypes.
Even with these options available to patients, there remains
a compelling need for new oral agents with improved efficacy
and tolerability for use as part of all-oral IFN-free combinations
containing drugs that target several different mechanisms of
action.
Results and Discussion
One of the most important features of the P2–P4 macrocyclic
class of HCV NS3/4a protease inhibitors is the P2-heterocycle.
Tremendous structural diversity is tolerated in this region, but
the specific identity of this group is critical to the broad geno-
type and mutant profile of next-generation inhibitors. As was
demonstrated with the publication of the X-ray crystal struc-
ture of several inhibitors bound in the NS3/4a active site,[23]
the identity of the P2-heterocycle has a significant impact on
the binding mode, and is likely responsible for the ability of
MK-5172 to maintain high affinity for the clinically important
gt1a mutant R155K. As is apparent in Figure 2A, this crystal
structure also reveals the possibility of an ordered water mole-
cule interacting with the 1-position nitrogen atom of the qui-
noxaline ring system. Although this type of water-mediated hy-
drogen bonding interaction has not been demonstrated in
other genotypes or mutant enzymes, it could be partly respon-
sible for the empirically observed increase in potency realized
with quinoxalines and 3-oxoquinolines relative to the isomeric
2-oxoquinolines.[19]
As has been detailed in several previous publications,
Merck’s molecular-modeling-derived strategy was inspired by
BILN-2061, but resulted in the development of an alternative[17]
macrocyclic core containing a novel P2–P4 linkage; this subse-
quently led to the discovery of vaniprevir[12,13] and the next-
generation NS3/4a protease inhibitor MK-5172 (Figure 1).[18,19]
MK-5172, in combination with the NS5A inhibitor MK-8742,[20]
recently demonstrated impressive clinical results, received
“breakthrough therapy” designation from the US Food and
Drug Administration (FDA),[21] and is currently in phase III clini-
cal development.
Prior to publication of the crystal structure, we did not have
an understanding of the effects that lead to the increased po-
tency observed with the P2-quinoxaline (and inclusion of the
1-position nitrogen atom in particular), and therefore we de-
cided to examine this phenomenon further by preparing addi-
tional P2-heterocycles containing acceptor groups at this posi-
tion of the heterocyclic ring (Table 1). Entry 1 shows the base-
line level of potency across our standard first-tier assays [gt1b,
gt3a, and gt1b mutants (R155K,[24] A156T, A156V, D168Y)] for
a simple unsubstituted P2-quinoxaline. Extension of the hydro-
gen bond acceptor site by one atom results in quinoline N-
oxide 2, which is nearly sevenfold more potent against gt3a
and maintains potency against the rest of the panel, indicating
that an acceptor atom external to the ring could be beneficial.
Poor oral exposure in rat pharmacokinetics (PK) experiments
limited the advancement of quinoline N-oxides, but further in-
creased our interest in pursuing related analogues. Replace-
ment of the NꢀO bond with a 4-hydroxyquinoline CꢀOH bond
(in 3) maintained good gt3a potency similar to that of qui-
noxaline 1 and also led to a flattening of the gt1b A156T/V po-
tency in contrast to the more typical two- to threefold shift.
Conversion into the 4-methoxyquinoline 4 led to a near 10-
fold loss in gt3a potency, whereas introduction of a carbonyl
group at this position (en-
In the continued pursuit of additional compounds with
next-generation profiles similar to that of MK-5172, we decided
to follow up on two previously disclosed observations. First,
during the development of the P2–P4 macrocyclic series lead-
ing ultimately to MK-5172, we discovered the gt3a-potency-en-
hancing effect of P2-quinoxalines or quinolines with a heteroa-
tom at the 1-position (red ’X’ in Figure 1).[19] In contrast to het-
erocycles that lack this feature, rings with a nitrogen atom at
this position had a higher level of broad genotype and mutant
enzyme activity, and we wanted to explore the generality of
this observation by preparing novel P2 groups that also pres-
ent a heteroatom in this region (red ’XꢀY’ in Figure 1). Second,
in 2008 we reported the effects of combining P1–P3 and P2–
P4 macrocycles to form fused 18-/15-membered bis-macrocy-
cles.[22] With the clinical success of MK-5172, we were also in-
terested to examine the effects of this type of ring system
within the context of more optimized P2 and P4 groups.
Herein we describe the discovery of two additional next-gener-
ation HCV NS3/4a protease inhibitors containing a novel P2-
quinazolinone and bis-macrocyclic ring system as the key
structural features.
tries 5–8) led to sub-nanomolar
gt3a potency regardless of the
specific heterocycle identity.
Figure 2B shows an overlay of
a model of isoquinolinone 5
and the X-ray structure of MK-
5172 in the gt1a R155K active
site, again indicating the possi-
bility of a direct or water-medi-
ated hydrogen bonding interac-
tion with residue 155. Changing
Figure 1. Structure of MK-5172 and general structure for new P2-heterocycles and bis-macrocycles.
the angle of the acceptor atom
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successful in identifying compounds that also show high liver
concentrations in other preclinical species, and was used to
identify both MK-5172 and vaniprevir. The ability to obtain
good systemic exposure in addition to liver exposure might
have an additional advantage, given some evidence for extra-
hepatic replication sites,[25] and was the strategy behind the
discovery of the HCV NS3/4a protease inhibitor MK-1220.[25]
Additional HCV NS3/4s protease inhibitor discovery efforts also
pursued this more balanced approach of optimizing for com-
pounds with both high preclinical liver and plasma exposures.
Further profiling (Table 2) of initial P2-quinazolinone lead 6
revealed a compound with excellent cellular activity (gt1b re-
plicon EC50 =3 nm), a small threefold shift in the presence of
50% NHS (EC50 =9 nm), and good rat liver exposure following
p.o. dosing (5 mgkgꢀ1 [liver]4h =9 mm), which is similar to the
level obtained with vaniprevir under the same conditions.[12]
Unfortunately, the plasma exposure at this dose was quite low
(0.04 mmh), and with additional analogues, the focus was in
optimizing for potency as well as rat liver and plasma expo-
sure. As we demonstrated earlier,[19,26] substituents on the P2-
heterocycle can have significant effects on potency as well as
rat PK. Introduction of a 7-methoxy group (in 12), which corre-
sponds to the same relative position as the methoxy group in
MK-5172, did not significantly improve either enzymatic or cel-
lular potency, and while the rat liver concentration at 4 h was
increased more than fourfold following a 5 mgkgꢀ1 oral dose,
the rat plasma exposure was slightly lower (0.01 mmh). Move-
ment of the methoxy group to the 8-position (in 13) slightly
improved gt1b A156 mutant potency relative to 12; however,
the rat liver concentration at 4 h fell nearly sevenfold, whereas
plasma exposure did not increase significantly. Other quinazoli-
none substituents and cyclic linker constraints were screened,
but without appreciable benefit to potency or rat plasma and
liver exposure relative to 6 and 12. For example, 14, containing
a 7-chloroquinazolinone P2 and a methylcyclopropyl carba-
mate in the linker region, maintained or slightly improved en-
zymatic potency, but had poor rat liver and plasma exposure.
In contrast to the small effects of substituents on the quinazo-
linone, the introduction of a methyl group into the cyclopropyl
acylsulfonamide[27,28] improved plasma exposure dramatically.
In comparison with 12, methylated analogue 15 led to a 70-
fold improvement in rat plasma AUC0–4h. Given the excellent
broad enzymatic potency, good cellular activity, and promising
initial rat PK profile, 15 (MK-2748) was selected for additional
profiling.
Figure 2. A) X-ray crystal structure of MK-5172 in gt1a R155K showing or-
dered water and possible hydrogen bonding interactions. B) Model overlay
of isoquinolinone 5 (green carbon scaffold) on the structure of MK-5172
shown in panel A.
by introduction of a sulfonyl group (in 9) led to a significant
loss in potency against gt3a and the gt1b mutants. Lastly, re-
moval of the fused phenyl ring (in 10) or shifting it to a bi-aryl
(in 11) decreased potency five- to tenfold against both gt3a
and gt1b mutant enzymes. Following the identification of sev-
eral novel P2-heterocycles with the potential for next-genera-
tion pan-genotype profiles and initial PK profiling (data not
shown), we decided to pursue further optimization of the qui-
nazolinone 6.
As we have discussed in several previous communica-
tions,[12,17,19] the plasma PK and oral bioavailability for HCV pro-
tease compounds can appear poor, despite high and sustained
liver concentrations; this is partially attributed to liver uptake
transport, such as organic anion transporting polypeptides
(OATPs). Because HCV replicates predominantly in the liver,
liver concentrations might be considered a primary driver for
efficacy.[25] Therefore, compounds were optimized for high liver
concentrations in preclinical species as part of the preliminary
PK evaluation. The initial PK assessment measured rat plasma
exposure (AUC0–4h) in addition to terminal liver concentrations
at 4 h following a 5 mgkgꢀ1 oral dose. This strategy has been
A more detailed PK study (Table 3) shows 15 to have a high
clearance (Clp) and moderate volume of distribution (Vd) in rat,
whereas it has low Clp and Vd values in dog. In both species,
15 has moderate bioavailability (~40% in rat, 27% in dog at 5
and 3 mgkgꢀ1, respectively). In rat, the liver concentrations are
maintained at a high level for extended periods. Following
a 5 mgkgꢀ1 dose of the potassium salt of 15, the rat liver con-
centration at 24 h is 28.9 mm, whereas plasma concentrations
are 0.017 mm, leading to a liver/plasma ratio ([L]/[P]) of 1700 at
24 h. Relative to the 50% NHS gt1b replicon EC50 value
(11 nm), liver concentration is maintained at >2600-fold excess
out to 24 h. The dog liver concentration (0.28 mm) of 15 was
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not as high as rat at 24 h, and
also the dog [L]/[P] exposure
ratio was only 2.8. The reason
for the species difference is un-
known, but might result from
saturation of uptake in dog liver
or species differences in tissue
binding. Compound 15 displays
excellent selectivity versus other
serine proteases (no activity
against elastase and trypsin,
176000-fold versus chymotryp-
sin) and against a broad Panlabs
screen (>100000-fold selectivi-
ty). Given the sum of data in
terms of excellent potency
against gt3 and gt1 mutant en-
zymes, favorable preclinical PK
Table 1. Identification of P2-quinazolinones.
No. P2-Heterocycle
Bond
Enzyme Inhibition Ki [nm][a]
*
1b
3a
R155K
A156T
A156V
D168Y
1
single <0.02ꢁ0
2.7ꢁ0.57 0.16ꢁ0
2.7ꢁ0.28
8.2ꢁ1.8 1.7[b]
properties, and
a clean off-
2
3
4
5
6
7
8
single
0.02ꢁ0.01 0.4ꢁ0.12 0.06ꢁ0.02
1.9ꢁ0.2
6.6[b]
ND[c]
target profile, 15 (MK-2748) was
selected for further clinical de-
velopment.
During the same time that
MK-2748 was being developed,
we had decided to re-investi-
gate the P1–P3/P2–P4 bis-mac-
rocyclic series[22] to determine if,
with more recently discovered
single <0.02ꢁ0
1.8ꢁ0.42 0.09ꢁ0.01
12.8ꢁ1.71 0.34ꢁ0.03
0.43ꢁ0.06 0.04ꢁ0.03
0.6ꢁ0.09 0.05ꢁ0.02
0.5ꢁ0.04 0.04ꢁ0.01
0.64ꢁ0.03 0.07ꢁ0
4.5ꢁ0.36
9.5ꢁ1.22
1.5ꢁ0.21
3.8ꢁ0.36 0.04ꢁ0
single
0.05ꢁ0
5.2ꢁ0.9
ND[c]
P2-heterocycles,
this
series
could also yield a compound
with the potential to be an ad-
ditional next-generation HCV
NS3/4a protease inhibitor with
a profile similar to that of MK-
5172. Given the synthetic com-
plexity inherent in this series,
we decided to simplify one
aspect and focus only on P2-
heterocycles present in previ-
ously discovered development
candidates or compounds that
had already demonstrated next-
generation profiles in P2–P4
mono-macrocycles (Table 4). In-
corporation of the isoindoline
present in MK-7009 (vaniprevir)
while maintaining a related P2–
P4 linker and the same P1–P3
linker as BILN-2061 leads to
compound 16, which has
<5 nm potency across our stan-
dard panel of gt1b, gt3a, and
gt1 mutant enzymes; however,
gt1b replicon potency (7 nm) is
significantly shifted in the pres-
ence of 50% NHS (58 nm) and
has very poor rat liver concen-
single <0.02ꢁ0
double <0.02ꢁ0
double <0.02ꢁ0
3.0ꢁ0.05 0.05[b]
0.92ꢁ0.17 3.5[b]
0.08[b]
2.8ꢁ1.06
2.4ꢁ0
5.0ꢁ0.02 0.06ꢁ0.01
double
0.03ꢁ0
0.08ꢁ0
5.2ꢁ0.07 ND[c]
9
single
47.5ꢁ0.71 1.15ꢁ0.21 115ꢁ7.1
ND[c]
ND[c]
10
double
0.05ꢁ0.01 11.0ꢁ1.4
0.29ꢁ0.08
7.4ꢁ1.5
39.4ꢁ6.1 0.45ꢁ0.08
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against gt1b A156T (41 nm).
However, in contrast to 16,
compound 17 has a high rat
liver concentration at 4 h
(15.8 mm), and similar to MK-
1220 itself, excellent rat plasma
exposure following oral dosing
Table 1. (Continued)
(4.5 mmh at 5 mgkgꢀ1).
A 2-
ethoxy-7-methoxyquinoline was
previously used[26,29] in an opti-
mized P2–P4 mono-macrocyclic
HCV NS3/4a inhibitor, but incor-
poration of the P1–P3 macrocy-
cle in this case did not lead to
significant benefit, but rather
maintained a similar profile to
that of the simpler mono-P2–P4
linker analogues. Next, we ex-
plored the effects of the 6-me-
thoxyquinoxaline present in
MK-5172 within the context of
No. P2-Heterocycle
Bond
Enzyme Inhibition Ki [nm][a]
R155K A156T
*
1b
3a
A156V
D168Y
ND[c]
11
single
0.02ꢁ0
2.9ꢁ0.42 0.10ꢁ0.01 13.5ꢁ3.5
24.5ꢁ2.1
[a] NS3/4a protease time-resolved fluorescence assay; potency values are the average ꢁSD of two or more iter-
ations unless otherwise specified. [b] Single measurement. [c] Not determined.
a
bis-macrocycle (compounds
trations at 4 h (0.2 mm) following a 5 mgkgꢀ1 p.o. dose. Com-
pound 17 has the same P2-heterocycle as MK-1220 and shows
good gt1b and gt3a potency, but has much lower potency
19–22). Both the ring size of the cyclic constraint in the P2–P4
linker and the substitution on the cyclopropylacylsulfonamide
were examined. As is evident from Table 4, all analogues dis-
Table 2. Optimization of P2-quinazolinones.
Compd
Enzyme Inhibition Ki [nm][a]
gt1b EC50 [nm][b]
Rat PK[c]
1b
3a
R155K
A156T
A156V
3.5[d]
D168Y
0.08[d]
0.13ꢁ0.02
0.07ꢁ0.01
ND
10% FBS 50% NHS AUC0–4h [mmh] [liver]4h [mm]
6
<0.02ꢁ0
<0.02ꢁ0
<0.02ꢁ0
0.02ꢁ0
0.6ꢁ0.09
1.2ꢁ0.68
0.43ꢁ0.07
0.84ꢁ0.12
0.05ꢁ0.02
0.06ꢁ0.02
0.04ꢁ0.01
0.07ꢁ0
0.92ꢁ0.17
2.4ꢁ1.6
3ꢁ1.4
1[d]
9ꢁ0
0.04
0.01
0.03
<0.01
0.7
9.0
41.0
6.0
12
13
14
15
7.1ꢁ1.4
10[d]
0.72ꢁ0.12
1.17ꢁ0.06
2.85ꢁ0.4
1.6ꢁ0.36
9[d]
13[d]
13[d]
3[d]
2.7
0.009ꢁ0.003 1.212ꢁ0.296 0.032ꢁ0.009 2.543ꢁ0.621 2.847ꢁ1.17 0.057ꢁ0.014 0.8ꢁ0.6
11ꢁ2.2
14.0
[a] NS3/4a protease time-resolved fluorescence assay; values are the average ꢁSD of two or more iterations unless otherwise specified. ND: not deter-
mined. [b] Cell-based gt1b replicon assay. [c] 5 mgkgꢀ1 dosed orally in PEG400 (n=2); calculated AUC based on 4 h experiment and liver concentration
after 4 h, single experiment. [d] Single measurement.
Table 3. Pharmacokinetic parameters for 15 (MK-2748).
Species
Clp
Vd
t1/2 [h][a]
F [%]
~40
Plasma
max [mm][b]
Liver
C
Plasma
Liver
[L]/[P] AUC
[a]
[mLminꢀ1 kgꢀ1
]
[Lkgꢀ1
]
C
24h [mm][b]
AUC0–1 [mmh][b]
AUC0–1 [mmh][b]
Rat
Dog
88ꢁ67
5.0ꢁ3.7
1.9ꢁ0.5
2.5ꢁ0.8
0.49ꢁ0.04
4.4ꢁ1.9
28.9ꢁ2.8
1.7
19.3ꢁ19.1
3635
46.9ꢁ41.1
2421
1.0ꢁ0.2
0.12ꢁ0.02
27ꢁ11
0.28ꢁ0.33
2.8ꢁ1.7
[a] Dosing i.v.: rat (2 mgkgꢀ1, n=3) and dog (1 mgkgꢀ1, n=3) in 50% PEG200/DMSO. [b] Dosing p.o.: rat (5 mgkgꢀ1, n=3) and dog (3 mgkgꢀ1, n=3) in
potassium salt, 10% Tween. Values are the average ꢁSD of n=3 in a single experiment.
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Table 4. Bis-macrocycles and identification of MK-6325.
Compd
Enzyme Inhibition Ki [nm][a]
gt1b EC50 [nm][b]
Rat PK[c]
1b
3a
R155K
A156T
A156V
D168Y
ND
10%FBS 50%NHS AUC0–4h [mmh] [liver]4h [mm]
16
17
18
19
20
21
22
0.02ꢁ0.01
0.04ꢁ0.01
0.04[d]
3.2ꢁ0.62
2.4ꢁ0.57
0.55[d]
1.35ꢁ0.43
0.73ꢁ0.1
0.39[d]
2.0ꢁ0.3
ND
7[d]
2[d]
2[d]
2[d]
2[d]
2[d]
58[d]
25[d]
13[d]
9[d]
0.61
4.5
0.03
0.2
<0.01
0.1
0.2
15.8
13.5
6.4
3.6
19
42ꢁ11
1.74ꢁ0.39
0.16ꢁ0.05
0.03ꢁ0.01
0.07ꢁ0.01
0.05ꢁ0.01
14[d]
23ꢁ0
0.2[d]
<0.02ꢁ0
0.16ꢁ0
0.24ꢁ0
0.64ꢁ0.13
0.59ꢁ0.05
0.48ꢁ0.11
0.85ꢁ0.22
1.58ꢁ0.28
0.63ꢁ0.12
0.04ꢁ0
0.18ꢁ0.02
0.03ꢁ0
0.46ꢁ0.03
0.28ꢁ0.02
9[d]
0.03ꢁ0
4[d]
0.005ꢁ0.002 0.263ꢁ0.107 0.013ꢁ0.005 0.418ꢁ0.147 0.568ꢁ0.209 0.036ꢁ0.014 1.1ꢁ0.8 10.5ꢁ3.1
0.77
43
[a] NS3/4a protease time-resolved fluorescence assay; values are the average ꢁSD of two or more iterations unless otherwise specified. ND: not deter-
mined. [b] Cell-based gt1b replicon assay. [c] 5 mgkgꢀ1 dosed orally in PEG400 (n=2); calculated AUC based on 4 h experiment and liver concentration
after 4 h, single experiment. [d] Single measurement.
Table 5. Pharmacokinetic parameters for 22 (MK-6325).
Species
Clp
Vd
[Lkgꢀ1
t
1/2 [h][a]
F [%]
Plasma
Cmax [mm][b]
Liver
C24h [mm][b]
Plasma
AUC0–1 [mmh][b]
Liver
AUC0–1 [mmh][b]
[L]/[P] AUC
[a]
[mLminꢀ1 kgꢀ1
]
]
Rat
Dog
33ꢁ18
4.0ꢁ3.2
0.5ꢁ0.1
3.8ꢁ1.5
2.3ꢁ0.3
~8
12ꢁ11
0.07ꢁ0.04
0.35ꢁ0.30
20ꢁ11
2.4
9.9ꢁ4.3
5925
27.1ꢁ9.6
2469
4.4ꢁ2.0
0.12ꢁ0.03
3.0ꢁ1.6
[a] Dosing i.v.: rat (2 mgkgꢀ1, n=3) and dog (1 mgkgꢀ1, n=3) in 50% PEG200/DMSO. [b] Dosing p.o.: rat (5 mgkgꢀ1, n=3) and dog (3 mgkgꢀ1, n=3) in
potassium salt, 10% Tween. Values are the average ꢁSD of n=3 in a single experiment.
played superior levels of potency with <0.5, <0.1, and
<0.7 nm activity against gt3a, gt1b R155K, and gt1b A156T, re-
spectively; gt1b replicon potency was also excellent, with
EC50 ꢂ10.5 nm in the presence of 50% NHS for all four ana-
logues. In contrast to their similar potency, rat PK screening
data could be used to differentiate the compounds. Following
a 5 mgkgꢀ1 p.o. dose, rat liver concentrations at 4 h ranged
from 3.6 to 43 mm, and oral exposure AUC0–4h varied widely
from <0.01 to 0.77 mmh. Fortunately, the highest liver and
plasma levels were provided by the same compound, 22 (MK-
6325), which contains the identical cyclopentanol carbamate
P2–P4 linker and methylcyclopropyl acylsulfonamide as in 15
(MK-2748).
posure at 24 h is 20 mm (>2000-fold the 50% NHS gt1b repli-
con potency), whereas plasma concentrations are 0.006 nm,
giving a liver/plasma ratio of >3300. Also similar to 15, the
liver-to-plasma exposures for 22 were not as high in dog as
they were in rat, which again might be attributed to saturation
of uptake or species differences in tissue binding. Compound
22 also displays excellent selectivity versus other serine pro-
teases (no activity against elastase and trypsin, 17000-fold
versus chymotrypsin) and against a broad Panlabs screen (>
80000-fold selectivity). In total, based on the data in terms of
gt1b, gt3a, and gt1 mutant enzyme potency along with prom-
ising preclinical PK properties and a clean off-target profile, 22
(MK-6325) was also chosen for continuation into clinical devel-
opment.
A more detailed PK study (Table 5) showed 22 to have mod-
erate Clp and Vd in rat and moderate Clp but low Vd in dog. In
both species, 22 has low oral bioavailability (~8% in rat, 12%
in dog at 5 mgkgꢀ1), but similar to 15, rat liver exposure is
maintained at a very high level for extended periods. Follow-
ing a 5 mgkgꢀ1 p.o. dose of the potassium salt of 22, liver ex-
To more fully assess the potential of both 15 (MK-2748) and
22 (MK-6325) as next-generation HCV NS3/4a protease inhibi-
tors, additional profiling was carried out across a wider panel
of genotypes and mutant enzymes in both biochemical and re-
plicon assay systems (Table 6). As can be seen from Table 6A,
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whereas MK-2748 also displays
Table 6. Broad genotype and mutant enzyme profiling for 15 (MK-2748) and 22 (MK-6325).
a
similar level of potency
A) Enzyme Inhibition IC50 [nm][a]
B) Replicon Potency EC50 [nm][b]
against genotype 2a/2b (EC50 <
4 nm) and gt5a (EC50 =1.4 nm)
while still maintaining good
gt3a potency (EC50 =15.8 nm).
Genotype
gt1a
gt1b
gt2a
gt2b
gt3a
gt4a
gt5a
15
22
Genotype
15
22
0.015ꢁ0.004
0.009ꢁ0.003
0.031ꢁ0.010
0.088ꢁ0.024
1.212ꢁ0.296
0.100ꢁ0.031
0.115ꢁ0.038
0.064ꢁ0.026
0.032ꢁ0.009
2.543ꢁ0.621
2.847ꢁ1.170
0.057ꢁ0.014
0.011ꢁ0.005
0.005ꢁ0.002
0.014ꢁ0.006
0.030ꢁ0.014
0.263ꢁ0.107
0.134ꢁ0.111
0.078ꢁ0.028
0.045ꢁ0.008
0.013ꢁ0.005
0.418ꢁ0.147
0.568ꢁ0.209
0.036ꢁ0.014
gt1a
gt1b
0.5ꢁ0.4
0.8ꢁ0.6
0.8ꢁ0.5
1.6ꢁ0.7
2.7ꢁ1.2
0.4ꢁ0.2
0.7ꢁ0.2
1.4ꢁ0.5
1.7ꢁ0.8
35.7ꢁ9.5
4.8ꢁ1.8
2.6ꢁ0.6
1.6ꢁ0.4
3.1ꢁ1.2
3.8ꢁ0.9
15.8ꢁ7.7
1.4ꢁ0.4
0.4ꢁ0.2
1.1ꢁ0.8
0.9ꢁ0.5
2.0ꢁ0.5
3.3[c]
0.6ꢁ0.2
0.4ꢁ0.3
1.0ꢁ0.1
0.8ꢁ0.2
5.5ꢁ1.3
1.7ꢁ0.6
1.7ꢁ0.6
2.2ꢁ0.5
4.0[c]
gt1a Q41R
gt1b Q41R
gt1b F43S
gt1a Q80K
gt1a R155K
gt1b R155K
gt1b A156S
gt1b A156T
gt1a D168A
gt1b D168A
gt1b D168V
gt2a
Conclusions
Optimization for next-genera-
tion-like HCV NS3/4a inhibitor
gt6a
gt1b R155K
gt1b A156T
gt1b A156V
gt1b D168Y
potency across a panel of sever-
al genotype and mutant en-
zymes along with selecting for
compounds that provide both
high liver levels and improved
gt2b
gt3a
gt5a
2.1ꢁ0.4
4.5ꢁ1.6
2.0ꢁ0.8
plasma exposure led to the dis-
covery and development of two
[a] NS3/4a protease time-resolved fluorescence assay. [b] Cell-based replicon assay. Potency values are the aver-
novel HCV NS3/4a inhibitor
age ꢁSD of three or more iterations unless otherwise specified. [c] Single measurement.
structural classes. Further opti-
mization of these classes led to
the identification of MK-2748
MK-2748 maintains biochemical potency <0.115 nm across
gt1–gt6, with the exception of gt3a, for which it is 1.2 nm. MK-
6325 is slightly more potent, with IC50 values <0.263 nm
across genotypes, and most being <0.1 nm. Table 6B lists the
potency of MK-2748 and MK-6325 across various gt1 mutant
enzymes in the replicon assay system. Similar to their enzymat-
ic profiles, both compounds display excellent replicon potency
across a panel of key gt1a (including R155K) and gt1b mutants,
with all EC50 values <5 nm, and only one exception: gt1b
A156T for MK-2748. Both compounds also display a very high
level of replicon potency against non-gt1 genotypes, with MK-
6325 maintaining sub-5 nm activity against gt2, gt3a, and gt5a,
and MK-6325, the distinguishing structural features of which
are a P2-quinazolinone and an 18-/15-bis-macrocyclic ring
system, which along with the addition of a methyl group to
the P1-cyclopropylacylsulfonamide, resulted in compounds
with broad genotype and mutant potency, selectivity, and pre-
clinical PK profile suitable for clinical development as next-gen-
eration HCV NS3/4a protease inhibitors.
Experimental Section
Compounds: Please refer to the Supporting Information for de-
tailed synthetic procedures. All compounds were prepared and
Scheme 1. Synthesis of 22 (MK-6325).
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Scheme 2. Synthesis of 15 (MK-2748).
tested at >95% purity, as determined by LC–MS. Although 22
(MK-6325) could be prepared via the bis-macrocyclization se-
quence detailed in our previous communication,[22] in practice, the
synthesis of 22 was carried out in 13 linear steps (20 total steps)
by starting from (2S,4R)-1-tert-butyl-2-methyl-4-[(3-chloro-7-me-
thoxyquinoxalin-2-yl)oxy]pyrrolidine-1,2-dicarboxylate (23), a key
intermediate in the synthesis of MK-5172 (Scheme 1). Following
base-mediated hydrolysis and coupling to commercially available
amine 24, the Boc group in 25 was removed, and a second amide
coupling, this time to commercially available acid 26, was carried
out to yield key bis-olefin 27. Based on the factors discovered at
Boehringer Ingelheim during the development of BILN-2061,[30] we
Boc-protected the amide NH group and then proceeded with the
ring-closing metathesis (RCM) reaction, which, after removal of the
two Boc protecting groups, yielded mono-macrocyclic amine 28 in
an excellent yield of 95% over three steps as a single isomer. Addi-
tion to activated carbonate 29 and vinylation led to the second
RCM precursor 30 in good yield. More dilute conditions and higher
catalyst loading was required to form the desired 18-membered
ring in moderate (67%) yield relative to the initial 15-membered
RCM product. However, after selective reduction of the more acti-
vated styryl olefin,[31] hydrolysis, and acylsulfonamide formation
with readily available sulfonamide 31, compound 22 (MK-6325)
was prepared in 18% overall yield.
amine 39, compound 15 (MK-2748) was synthesized in 50% yield
over 11 linear steps.
In vitro assays: Enzymatic and replicon assays were performed as
previously described.[18]
Pharmacokinetic studies: Studies were performed as previously
described[18] in both rat and dog, and protocols were approved by
the Merck Research Laboratory Institutional Animal Care and Use
Committee.
Acknowledgements
We thank Dr. Charles W. Ross III and Ms. Joan S. Murphy for
high-resolution mass spectrometry data and Sandor L. Varga for
interpretation of NMR spectra.
Keywords: antiviral agents · hepatitis C · macrocycles · MK-
2748 · MK-6325
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Received: December 23, 2014
Published online on && &&, 0000
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M. T. Rudd,* J. W. Butcher, K. T. Nguyen,
C. J. McIntyre, J. J. Romano, K. F. Gilbert,
K. J. Bush, N. J. Liverton, M. K. Holloway,
S. Harper, M. Ferrara, M. DiFilippo,
V. Summa, J. Swestock, J. Fritzen,
S. S. Carroll, C. Burlein, J. M. DiMuzio,
A. Gates, D. J. Graham, Q. Huang,
S. McClain, C. McHale, M. W. Stahlhut,
S. Black, R. Chase, A. Soriano,
Breakthrough antivirals: We describe
the discovery of two hepatitis C virus
(HCV) NS3/4a protease inhibitors with
excellent potency against a broad geno-
type and mutant range. It is anticipated
that such wide-scope activity will be
a prerequisite for successful clinical de-
velopment of next-generation antiviral
agents.
C. M. Fandozzi, A. Taylor, N. Trainor,
D. B. Olsen, P. J. Coleman, S. W. Ludmerer,
J. A. McCauley*
&& – &&
P2-Quinazolinones and Bis-
Macrocycles as New Templates for
Next-Generation Hepatitis C Virus
NS3/4a Protease Inhibitors: Discovery
of MK-2748 and MK-6325
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