Discovery of MK-8831, A Novel Spiro-Proline Macrocycle as a Pan-Genotypic HCV-NS3/4a Protease Inhibitor

Article abstract of DOI:10.1021/acsmedchemlett.5b00425

We have been focused on identifying a structurally different next generation inhibitor to MK-5172 (our Ns3/4a protease inhibitor currently under regulatory review), which would achieve superior pangenotypic activity with acceptable safety and pharmacokinetic profile. These efforts have led to the discovery of a novel class of HCV NS3/4a protease inhibitors containing a unique spirocyclic-proline structural motif. The design strategy involved a molecular-modeling based approach, and the optimization efforts on the series to obtain pan-genotypic coverage with good exposures on oral dosing. One of the key elements in this effort was the spirocyclization of the P2 quinoline group, which rigidified and constrained the binding conformation to provide a novel core. A second focus of the team was also to improve the activity against genotype 3a and the key mutant variants of genotype 1b. The rational application of structural chemistry with molecular modeling guided the design and optimization of the structure-activity relationships have resulted in the identification of the clinical candidate MK-8831 with excellent pan-genotypic activity and safety profile.

Full text of DOI:10.1021/acsmedchemlett.5b00425

Letter
pubs.acs.org/acsmedchemlett
Discovery of MK-8831, A Novel Spiro-Proline Macrocycle as a Pan-
Genotypic HCV-NS3/4a Protease Inhibitor
Santhosh F. Neelamkavil,* Sony Agrawal, Thomas Bara, Chad Bennett, Sathesh Bhat, Dipshikha Biswas,
Linda Brockunier, Nicole Buist, Duane Burnette, Mark Cartwright, Samuel Chackalamannil, Robert Chase,
Mariappan Chelliah, Austin Chen, Martin Clasby, Vincent J. Colandrea, Ian W. Davies, Keith Eagen,
Zhuyan Guo, Yongxin Han, John Howe, Charles Jayne, Hubert Josien, Stacia Kargman,
Karen Marcantonio, Shouwu Miao, Randy Miller, Andrew Nolting, Patrick Pinto, Murali Rajagopalan,
Rebecca T. Ruck, Unmesh Shah, Aileen Soriano, Donald Sperbeck, Francisco Velazquez, Jin Wu, Yan Xia,
and Srikanth Venkatraman
Merck Research Laboratories, Kenilworth, New Jersey 07033, United States
S
* Supporting Information
ABSTRACT: We have been focused on identifying a structurally different next generation inhibitor to MK-5172 (our Ns3/4a
protease inhibitor currently under regulatory review), which would achieve superior pangenotypic activity with acceptable safety
and pharmacokinetic profile. These efforts have led to the discovery of a novel class of HCV NS3/4a protease inhibitors
containing a unique spirocyclic-proline structural motif. The design strategy involved a molecular-modeling based approach, and
the optimization efforts on the series to obtain pan-genotypic coverage with good exposures on oral dosing. One of the key
elements in this effort was the spirocyclization of the P2 quinoline group, which rigidified and constrained the binding
conformation to provide a novel core. A second focus of the team was also to improve the activity against genotype 3a and the
key mutant variants of genotype 1b. The rational application of structural chemistry with molecular modeling guided the design
and optimization of the structure−activity relationships have resulted in the identification of the clinical candidate MK-8831 with
excellent pan-genotypic activity and safety profile.
KEYWORDS: Antiviral, HCV, NS3/4a, genotype 3a, pan-genotypic, macrocycle, MK-5172, MK-8831
major milestone in the field as it significantly improved the
n the 25 years that have passed since the first report of
̈
Icloning of hepatitis C virus (HCV), the treatment of chronic sustained virological response (SVR) up to 75% for naive HCV
genotype 1 patients and shortened the treatment time.4,5
Recent FDA approval of Sofosbuvir (Sovaldi; HCV NS5B
polymerase inhibitor) and other protease inhibitors have shown
promise to further improve the cure rates, tolerability, and
shorten treatment for HCV patients.6−8 At Merck, we have
recently reported impressive cure rates with MK-5172 (NS3/4a
protease inhibitor) in combination with MK-8742 (NS5A
inhibitor), resulting in “breakthrough” designation from FDA
and is currently under regulatory review.9 Recent focus across
hepatitis C virus has undergone dramatic changes.1 Approx-
imately 170−200 million people worldwide are chronically
infected with HCV with majority infected by genotype 1
(∼70% of all cases of HCV in United States), 2, and 3.2 Among
the six major genotypes (gt) 1−6 that have so far been
identified, gt1 is the most prevalent worldwide comprising 83.4
million cases (46.2% of all HCV cases) and gt3 the next most
prevalent globally (54.3 million, 30.1%). For several years the
standard of care was pegylated interferon plus rivabarin, which
had a cure rate of only ∼45% for genotype (gt) 1 affected
patients with a treatment period of 24−48 weeks and associated
with difficult side effects.3 The first approval of direct-acting
antiviral agents (boceprevir and telaprevir) was considered a
Received: November 9, 2015
Accepted: December 22, 2015
© XXXX American Chemical Society
A
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Figure 1. (a) Comparison of the models of acyclic and spirocyclized P2-proline inhibitors and their interactions with H57. (b) Conformational
analysis of the P2 side chains of acyclic compound 1 and spiro compound 2. The bound conformation is colored green. Only low energy conformers
(dE < 2 kcal/mol) are shown. (c) Overlay of 5−7-membered spiro-cyclic rings with the 6-membered ring in green.
Table 1. Enzyme and Replicon Data Showing Potency Improvements for the Spiro-Prolines 2 and 3 When Compared to Acyclic
Compound 1 for gt1b, gt3a, and gt1 Resistant Variants
the pharmaceutical industry has been to combine compounds
from different classes of HCV direct acting antivirals (DAAs)
that would offer an all-oral interferon free treatment option. In
this context there is a continuing need for potent pan-genotypic
NS3/4a protease inhibitors with high barrier to resistance
against gt variants.
We have previously reported the discovery of MK-5172
(P2−P4 HCV macrocyclic protease inhibitor) and newer pan-
genotypic quinoline analogues as protease inhibitors.10−12
Several P1−P3 HCV protease inhibitors, e.g., simprevir,
danoprevir, asunaprevir, and faldaprevir, have also been
reported by others.7,13−15 While earlier protease inhibitors are
highly effective for gt1 patients, they have limited efficacy
against gt3a and multiple resistant variants for gt1b. Hence, we
were interested to follow-up MK-5172 with a compound that
would be structurally different and further improve potency
specifically against genotype 1 (gt1) resistant variants and
genotype 3 (gt3) but also provide robust pan-genotypic activity.
In our efforts leading to the back-up of MK-5172, we decided
to employ a molecular modeling strategy and focus on novel
variants of P2 quinolines. We have previously reported that
modifying the P2 quinoline region could improve gt3a
activity.11 We were interested to see if we could impart
structural rigidity to these optimized P2 groups and possibly
identify a novel alternative core with significant potency
improvements. Our efforts started with the previously reported
B
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acyclic P1−P3 compound 1 with a rational modeling approach
and a focus on imparting structural modifications focused on
the P2 quinoline region to improve potency specifically on gt3a
and gt1.16 After carefully looking at several constrained models
of P2, we hypothesized that a spirocyclization of the quinoline
moiety onto the proline could make favorable van der Waals
contacts with histidine (H57) an invariant catalytic residue,
which may result in an improved mutant profile. Spirocycliza-
tion would also impart greater conformational rigidity to the
molecule and may provide an advantage with reduced entropic
cost of binding by biasing it toward the bioactive conformation
(Figure 1a). We chose the 2-methyl quinolone 2 for
spirocylization as modeling indicated that the methyl group
could have favorable hydrophobic interactions with A156 in the
enzyme.
Figure 2. Overlay of compound 3 in the binding site of the protease.
To test our hypothesis we performed a conformational
analysis and molecular dynamics simulations of the open chain
and the spirocyclized P2. It was nice to see that though multiple
conformers exist below 2 kcal for the acyclic version 1, only two
low energy conformers are available for the spiro compound 2
(Figure 1b). It is noteworthy that conformational analysis of
the P2 groups, while constraining the rest of the inhibitor in the
bound conformation, indicates that the bound conformation of
P2 is essentially the lowest energy conformations for both
inhibitors 1 and 2. In addition, different ring sizes 5−7 were
explored using molecular modeling, and the 6-membered ring
was the apparent choice to mimic the parent acyclic P2 (Figure
1c).
The enzyme and replicon data of the linear compound 1 and
spiro 2 are compared in Table 1. As can be seen from the data,
the spiro-cyclization of the P2 groups to proline improved the
potency of genotype 1b, 3a by ∼80-fold, and the overall
potency against key 1b mutants. With the proof of concept that
improved conformational rigidity results in improved pan-
genotypic profile of 2, we decided to see if we can further
improve the potency of the spirocyclic proline analogue by
forming a P1−P3 macrocycle. As described before, several P1−
P3 macrocycles have been reported to have improved potency
and pharmacokinetic properties, and we reasoned that a
macrocycle of 2 would further boost pan-genotypic potency
of this spiro-proline hit.13−15 With this in mind, 3 was
synthesized and as can be seen from the data in Table 1,
compound 3 displayed excellent potency profile with picomolar
activity against 1b and 8-fold improvement in 3a in the enzyme
panel. Compound 3 also showed significantly improved
potency profile against resistant associated variants (RAV) of
1b like R155K, A156T, A156V, and D168Y. The replicon assay
also showed similar potency boost across the 1b wild type and
the associated RAVs.
Differences in genotype 1−3 are seen close to P1−P4 region
and hence most of the previously reported P2−P4 macrocycle
inhibitors interact with A156 and its mutation to threonine
results in resistance. By moving to a spiro-macrocycle, which
goes via P1−P3, we were able to improve potency against
A156T and also genotype 3a as shown in Figure 2 of the
compound 3 in the protease binding site. It was particularly
gratifying to see that with rational structure-based drug design,
the combination of spiro-ring formation and macrocyclization
had resulted in a compound with excellent pan-genotypic
activity. Having achieved excellent in vitro profile with 3, our
next goal was to assess the pharmacokinetic properties of this
compound. Unfortunately, we found that compound 3 gave
very poor exposures after oral administration. At 5 mpk, the
compound showed poor AUC(0−24 h) of 0.14 μM·h, short t1/2
= 0.9 h, and poor bioavailability of 4%. As HCV targets the
liver, the concentration of the drug in liver was always
measured and served as an important criterion for advance-
ment. However, this compound had negligible liver levels at 24
h.
Our efforts to balance pharmacokinetic profile and potency
of compound 3 were mostly focused on the P2 aromatic region
and P4 carbamates as some of the previous reported structure−
activity relationships (SARs) from us and our peers had already
shown the methyl cyclopropyl group (P1′) to be an optimal
group for binding.14 The P1−P3 macrocycle was also designed
based on modeling and had the optimized chain length to avoid
any steric interactions related loss in potency.17 For SAR
purposes, we mainly focused on balancing gt3a potency with rat
AUC as activity against this genotype was highly sensitive to
changes to the P2 or P4 regions. Though we did make
significant functional group modifications, Table 2 below
highlights only the compounds that were the key breakthroughs
as we tried to optimize the properties to identify a clinical
candidate. We reasoned that the methyl group in the quinolone
could be a liability to oxidative metabolism and when the
methyl group in 3 was converted to cyclopropyl 4 we were
pleased to see the first hint of oral exposure, but it came with
reduced gt3a activity. When we introduced a trifluoromethyl
group in the quinoline 5 and changed the t-butyl to cyclopentyl
carbamate in P4, we had the first example that had a good
balance of oral exposures and gt3 activity. The second key
functionality that made a big improvement to potency was a
methoxy group on quinoline as can be seen in compound 6 but
again resulted in a loss in plasma exposure. We also found the
isobutyl carbamate to be a better group at improving rat AUC
while maintaining good gt3a potency. By combining the three
key functionalities that we had identified [(i) trifluoromethyl,
(ii) methoxy group on quinoline, and (iii) isobutyl carbamate]
we discovered compound 10, which had a favorable balance of
potency and plasma exposures in both rat and dog and was later
identified as the preclinical candidate MK-8831 (Table 2).
The synthesis of compound 10 is shown in Scheme 1.
Commercially available bromide 11 was converted to a borate,
which was then treated with mCPBA mediated conditions to
generate the phenol 12. Compound 12 was then treated under
tin mediated conditions to obtain the important precursor
ketone 13. The ketone was then cyclized with the previously
reported macrocyclic prolinone 13a under highly optimized
conditions, employing benzoic acid and pyrrolidine.18 While
C
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chloride under standard conditions and reduced under a novel
nickel boride mediated radical conditions to obtain compound
16. This was a key reaction as other attempts to obtain 16 with
hydrogenation or reductive conditions always led to the
reduction of the double bond in the macrocycle. The sequence
to compound 10 then involved hydrolysis of the ester 16 to
acid and coupling with cyclopropyl-methyl sulfonamide
followed by deprotection of the Boc group and treatment
with isopropyl chloroformate to obtain compound 10 (MK-
8831).
Table 2. SAR of P2 and P4 Groups: Comparison with gt3a
Potency and Rat AUC
The activities against various genotypes and the gt1 resistant
variants comparing MK-8831 with our clinical compound MK-
5172 are shown in Table 3. As can be seen MK-8831 had
Table 3. Comparing MK-8831 and MK-5172 Potency (IC50,
nM) Across an HCV NS3/4A Enzyme and Replicon
Genotype Panel
genotype
(GT)
assay
MK-8831 MK-5172
HCV NS3/4a enzyme assay IC50
(nM)
1a
1b
0.009
0.004
0.010
0.483
2.760
0.023
0.413
0.7
0.007
0.004
0.021
3.917
5.511
0.105
0.690
0.3
1b R155K
1b A156T
1b A156V
1b D168Y
3a
1a
1b
2a
2b
3a
HCV NS3/4a replicon assay EC50
(nM)
0.8
0.3
0.9
1.2
3.4
5.0
1.7
7.2
a
Scheme 1. Synthesis of MK-8831
excellent activity in enzyme and replicon assays and had pan
coverage of the prominent resistant genotypes and when
compared with our best-in-class protease inhibitor MK-5172,
MK-8831 showed significant improvements in potencies for
gt1b RAVs like A156T and D168Y. Most importantly in the
replicon assays shown in Table 3, MK-8831 showed >4-fold
improvement over genotype 3a in comparison to MK-5172.
MK-8831 showed good pharmacokinetic profile with oral
bioavailability in both rat and dog of 31 and 17%, respectively.19
It was highly protein bound in both species, but the high dose
PK showed good margin for us to do safety studies. For human
dose predictions we mainly wanted to obtain good coverage for
gt1 and 3a. For this purpose we assumed a worst case scenario
of 100% serum bound EC90 values as our criteria for a projected
human Ctrough. We saw that in 100% NHS (normal human
serum) the EC90 values for MK-8831 ranged from 60 to 90 nM
(gt1a = 68, 1b = 20, 2a = 60, and 3a = 90). We decided to aim
for a human dose that would match the serum adjusted EC90
values at Ctrough (90 nM) and Cmax, which would be ten times
that at 900 nM. Based on an allometric scaling mainly using dog
clearance and Vd we made a preliminary human PK prediction
a
(hupred: CL= 0.2 mL/min/kg, Vd = 0.1 L/kg, Foral = 15%, t1/2
=
Reagents and conditions: (a) LDA, B(OCH3)3, THF, −78 °C; (b)
mCPBA, NaHCO3, CH3CN; (c) Pd(PPh3)4, 1,4-dioxane, 120 °C; (d)
compound 2, pyrrolidine, benzoic acid, 55 °C; (e) NaBH4 (f) MsCl,
Et3N; (g) NaBH4, NiCl2·6H2O, (h) LiOH.H2O; (i) cyclopropylmethyl
sulfonamide, CDI, DBU; (j) (i) 4 N HCl, (ii) i-BuOCOCl, Et3N.
5 h) for a projected efficacy Cmax of 900 nM. Our human dose
projections show that a clinical dose of ∼35−100 mg (MRT ≈
7 h) could yield a target plasma trough of 90 nM. Moving on to
safety, MK-8831 had excellent off-target profile. It was clean
against the Cyp enzymes (3A4, 2C9, 2D6 up to 50 μM and
2D8 up to 20 μM) and did not show any negative results in
mutagenicity studies and in the AMES assays. Compound 10
showed a clean profile in a reproductive toxicity assay up to 300
initial conditions gave very poor yields, the optimized methods
gave 14 in >65% yield and high levels of diastereoselectivity (dr
= 99:1). The ketone of compound 15 was converted to
D
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Untreated Chronic HCV Genotype 1 Infection. N. Engl. J. Med.
2011, 364, 1195−1206.
μM and also in the micronucleus induction assay. We also
performed a standard rat/dog telemetry study and found that it
was clean in rats and dogs up to 40 mpk with 35× and 366×
exposure multiples (EM). In conscious telemetered dogs there
were no effects on heart rate, blood pressure, ECG parameters,
respiratory function, or body temperature. The three day safety
studies performed in rats for MK-8831 achieved excellent
exposures at 400 mkd (mg/kg/day) with no safety issues with
liver concentration at 134 μM (149× EM).
In summary, based on rational computational modeling and
structure-guided SAR designs, we were able to discover a novel
spiro-proline scaffold, which was then optimized to obtain MK-
8831 with excellent pangenotypic profile and good coverage
over the highly resistant 1b variants like A156T, A156V,
R155K, and D168Y as well as gt3a. Based on good
pharmacokinetic profile and excellent safety, MK-8831 was
selected as our preclinical candidate and entered Phase 1
studies. Further clinical data, process development and other
SAR studies on MK-8831 will be disclosed in the near future.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.5b00425.
■
S
1
Synthetic experimental details including H NMR and
mass spectral data for selected compounds, description of
primary biological assays, molecular modeling protocols,
and PK data (PDF)
AUTHOR INFORMATION
Corresponding Author
*Phone: 908-740-4062. E-mail: santhosh.neelamkavil@merck.
com.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors would like to thank Dr. Ann Weber, Dr. Joseph
Vacca, and Dr. Chris Hill for their support of this program. We
also thank Dr. Alexei Buevich for NMR support.
(12) Rudd, M. T.; Butcher, J. W.; Nguyen, K. T.; McIntyre, C. J.;
Romano, J. J.; Gilbert, K. F.; Bush, K. J.; Liverton, N. J.; Holloway, K.
M.; Harper, S.; Ferrara, M.; DiFilippo, M.; Summa, V.; Swestock, J.;
Fritzen, J.; Caroll, S. S.; Burlein, C.; DiMuzio, J.; Gates, A.; Graham, D.
J.; Hang, Q.; McClain, S.; McHale, C.; Stahlhut, M.; Black, S.; Chase,
R.; Soriano, A.; Fandozzi, C.; Taylor, A.; Trainor, N.; Olsen, D.;
Coleman, P.; Ludmerer, S.; McCauley, J. A. 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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ABBREVIATIONS
■
HCV, hepatitis C virus; SVR, sustained virological response;
DAA, direct acting antivirals; SAR, structure−activity relation-
ship; gt, genotype; AUC, area under the curve
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F
DOI: 10.1021/acsmedchemlett.5b00425
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