Development of potent macrocyclic inhibitors of genotype 3a HCV NS3/4A protease

Article abstract of DOI:10.1016/j.bmcl.2012.08.106

A series of macrocyclic compounds containing 2-substituted-quinoline moieties have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K mutant activity while maintaining the high rat liver exposure. Cyclization of the 2-substituted quinoline substituent led to a series of tricyclic P2 compounds which also display superb gt3a potency.

Full text of DOI:10.1016/j.bmcl.2012.08.106

Bioorganic & Medicinal Chemistry Letters 22 (2012) 7201–7206
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Development of potent macrocyclic inhibitors of genotype 3a HCV
NS3/4A protease
Michael T. Rudd a, , John A. McCauley a, Joseph J. Romano a, John W. Butcher a, Kimberly Bush a,
⇑
Charles J. McIntyre a, Kevin T. Nguyen a, Kevin F. Gilbert a, Terry A. Lyle a, M. Katharine Holloway d,
Bang-Lin Wan c, Joseph P. Vacca a, Vincenzo Summa e, Steven Harper e, Michael Rowley e
Steven S. Carroll b, Christine Burlein b, Jillian M. DiMuzio b, Adam Gates b, Donald J. Graham b
Qian Huang b, Steven W. Ludmerer b, Stephanie McClain b, Carolyn McHale b, Mark Stahlhut b
Christine Fandozzi c, Anne Taylor c, Nicole Trainor c, David B. Olsen b, Nigel J. Liverton a
a Department of Medicinal Chemistry, Merck Research Laboratories West Point, PA 19486, USA
b Department of Antiviral Research, Merck Research Laboratories West Point, PA 19486, USA
c Department of Drug Metabolism, Merck Research Laboratories West Point, PA 19486, USA
d Chemistry Modeling and Informatics, Merck Research Laboratories West Point, PA 19486, USA
e Department of Medicinal Chemistry, IRBM, Merck Research Laboratories, Rome, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 7 September 2012
A series of macrocyclic compounds containing 2-substituted-quinoline moieties have been discovered
and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K mutant activity while
maintaining the high rat liver exposure. Cyclization of the 2-substituted quinoline substituent led to a
series of tricyclic P2 compounds which also display superb gt3a potency.
Keywords:
Hepatitis C
NS3/4A protease
Macrocycle
Ó 2012 Elsevier Ltd. All rights reserved.
Alkoxyquinoline
P2–P4 linker
Hepatitis C is an infection caused by the hepatitis C virus (HCV)
that affects 130–170 million people worldwide and is the leading
indication for liver transplantation.1,2 Prior to 2011, the standard
macrocyclization strategy11 with a linker from P2 to P4 (Fig. 1),
exemplified by vaniprevir,12,13 MK-1220,14 and MK-5172.15,16 As
we have previously published, prior to the development of vanipre-
vir, optimization for genotype 1b potency initially led to compound
111 (Fig. 1), which has picomolar potency (1b Ki = 0.04 nM), good
cellular activity (1b replicon IC50 = 4.5 nM)11 and excellent liver
exposureinratfollowinga5 mg/kgoraldose([liver]4h = 18,600 nM).
Obtaining high and sustained liver exposure may be critical to the
success of any anti-HCV compound because the primary HCV
treatment for HCV was co-dosing with Pegylated IFN-a and Ribavi-
rin for up to one year, and along with producing severe side-effects,
this regimen is only moderately effective.3,4 The development of
antivirals which would inhibit key steps in the viral replication
process has been a major focus in the efforts to improve this
treatment. One such target that is critical for viral replication is
the serine protease HCV NS3/4A.5,6 Boehringer–Ingelheim initially
established clinical proof of concept for inhibition of HCV NS3/4a
protease with the macrocycle BILN-2061,7 and more recently both
Merck (SCH-503034, boceprevir9) and Vertex (VX-950, telaprevir8)
P2
N
O
N
O
O
have gained FDA approval for a-keto-amide HCV NS3/4A inhibitors
used in combination with the previous standard of care.
O
O
O
O
O
O
N
N
While a number of research programs have identified other HCV
NS3/4a protease inhibitors10 based upon the P1-P3 macrocyclic sys-
tempresentinBILN-2061, ourprogramhasfocusedonanalternative
series of HCV NS3/4A protease inhibitors utilizing a different
H
N
H
S
S
HN
O
HN
N
N
O
N
O
O
O
O
H
H
P4
O
O
P1
P3
Vaniprevir (MK-7009)
1
⇑
Corresponding author. Tel.: +1 215 652 9727; fax: +1 215 652 3971.
E-mail address: michael_rudd@merck.com (M.T. Rudd).
Figure 1. Merck developed P2–P4 macrocyclic HCV protease NS3/4a inhibitors.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.08.106

7202
M. T. Rudd et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7201–7206
ome with significant genetic heterogeneity and can be grouped
O
N
O
O
O
N
O
into 6 major genotypes (gt). The major genotype in the United
States is genotype 1, with genotypes 2 and 3 representing sizeable
populations as well. While 1 and vaniprevir are quite potent
against gt 1, they both are less active against gt 3a (1 gt3a
Ki = 475 nM; vaniprevir gt 3a Ki = 54 nM). This modest potency
motivated our efforts towards the identification of potential sec-
ond-generation compounds with improved gt 3a activity and
which maintain excellent cellular (replicon with 10% FBS/50%
NHS) potency and high liver exposure in preclinical species. We re-
cently published the strategy which led to the identification of MK-
5172.15,16 Herein, we disclose the discovery of a different series of
compounds with excellent potency against both genotype 1b and
3a.
O
O
O
O
O
O
N
N
H
N
H
N
S
S
HN
O
N
HN
O
N
N
O
O
H
H
O
O
2
3
nM
<0.16
5.8
nM
<0.16
17
1b Ki
3a Ki
1b Ki
3a Ki
Rat PK (5 mg/kg, oral)
[Liver] 4h
Rat PK (5 mg/kg, oral)
[Liver] 4h
304
41,000
In the context of our quinoline/isoquinoline (e.g., 1) P2–P4 mac-
rocycles we noticed that 2-phenylquinolines tended to produce
inhibitors with improved genotype 3a potency relative to bench-
mark compound 1. For example, 2 and 3 have significantly im-
proved genotype 3a potency (Ki = 6-17 nM) relative to 1, as well
as good liver exposure in the case of carbamate 3 (Fig. 2).
Since a major difference between these compounds and 1 is the
presence of a phenyl ring on the P2-heterocycle, we decided to
examine the effect of various substituents at this position.
In order to fully explore the SAR at the 2-position, we needed to
generate a large number of analogs, and using the classic Conrad–
Limpach quinoline synthesis18 used to prepare 2 and 3, the substi-
tuent in the 2-position is installed in the first step (Scheme 1). Uti-
lization of this synthesis would require an additional 9 steps to
complete each analog, We hoped to avoid this inefficiency by
developing a more versatile route which introduced the 2-substi-
tuent near the end. We envisioned that 4 could serve as a common
intermediate to introduce a variety of groups in the 2-position
(Scheme 2). These intermediates could then be transformed into
the desired compounds in two straightforward steps. For the initial
SAR studies, the carbamate linker was chosen based upon the high
liver exposure obtained with compound 3 (Fig. 2).
In practice, we began with a regioselective hydroxyquinolone
formation,19 followed by chemoselective alkylation20 at the 4-posi-
tion with brosylate 821 to give 4 as the only isolable mono-alkyl-
ated product (Scheme 3). Removal of the Boc group, HATU
coupling with 10,22 and vinylation with Molander’s vinyl trifluo-
roborate reagent23 led to intermediate 11. Ring-closing metathe-
sis24 using the Zhan 1B catalyst25 then produced the desired
macrocycle in good yield. Hydrogenation of the styrene double
bond yielded key intermediate 4 in 7 steps with an overall yield
of 26%.
Figure 2. Genotype 3 leads with improved potency.
O
O
O
N
Ar
O
NH2
a
O
Ar
Br
Br
OH
Scheme 1. Reagents and conditions: (a) polyphosphoric acid, heat.
replication site is in the liver,17 and optimizing for high liver concen-
trations in preclinical species became the focus of our preliminary
pharmacokinetic studies.
As an initial assessment of liver exposure, our standard practice
was to measure the concentration of compound present in rat liver
4 h after a 5 mg/kg oral dose. HCV has a positive-strand RNA gen-
H
O
O
N
O
O
O
N
O
R
Selective alkylation
or
O
Tf2O, then cross-coupling
CO2Me
O
N
2) LiOH
3) 6, HATU
O
H
N
O
N
H
N
S
O
HN
N
O
O
O
H
O
O
O
4
5
S
H2N
HCl
N
O
6
H
Scheme 2. Strategy for rapid synthesis of 2-substitutedquinoline analogs.
BsO
H
N
8
O
O
O
NH2
OH
H
N
CO2Me
O
O
N
Br
Br
Boc
a
O
O
O
b
Br
9
OH
O
7
HO
CO2Me
N
Boc
H
N
O
c,d, e
O
f, g
O
4
H
N
CO2Me
N
CO2H
H
O
N
O
O
10
O
11
Scheme 3. Reagents and conditions: (a) 1 equiv POCl3, 105 °C, 1 h, neat (66%); (b) NMP, Cs2CO3 (53%); (c) EtOH, Et3N, 5% Pd(dppf)Cl2, (CH2@CH2BF3)K, reflux (99%); (d) HCl/
dioxane; (e) HATU, DMF, DIEA (82% over two steps); (f) 10% Zhan 1b, DCE, 45 °C (99%); (g) 5% Pd/C, H2, EtOH (92%).

M. T. Rudd et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7201–7206
7203
Table 1
2-Aryl-, heteroaryl-, and aminoquinoline SAR
O
N
O
OTf
O
O
N
O
R
O
CO2Me
O
N
O
N
H
H
O
S
O
HN
N
N
N
O
O
H
O
O
12
5a-5j
#
R
1b Ki (nM)a
3a Ki (nM)a
1b replicon IC50 (nM)b
[liver]4h (l
M)c
10% FBS
50% NHS
5a
5b
5c
0.05
0.07
0.07
21
18
78
3.6
28
9.9
6.1
6.7
O
O
3.0
6.0
25
19
5d
5e
0.09
0.18
62
29
7.0
11
31
6.3
—
O
F
110
5f
—
55
27
92
90
0.2
N
O
5g
NH
0.09
5.4
1.6
<0.005
N
5h
5i
0.03
0.07
0.12
4.3
7.5
7.6
5.0
5.0
39
27
42
0.1
—
O
26
N
H
N
5j
1200
a
b
c
NS3/4a protease time-resolved fluorescence assay.
Cell-based replicon assay.
5 mg/kg dosed orally in PEG400 (n = 2, rat), liver levels after 4 h.
In order to access products via cross-coupling and nucleophilic
simple alcohols participated in triflate-displacement reactions or
palladium-catalyzed C–O cross-couplings. Therefore, we started
with quinolone 4 and utilized a series of oxygen-selective alkyla-
tions to access a range of 2-alkoxyquinolines (see Supplementary
data for details). Simple alkyl ethers such as methyl and ethyl are
readily available through use of Meerwein-type reagents in the ab-
sence of base which leads to nearly exclusive O-alkylation.28 More
functionalized ethers can be selectively accessed through the Mits-
unobu reaction29 or alkylation of alkyl halides in the presence of
silver salts.30
As Table 2 illustrates, a variety of 2-alkoxyquinolines possess
excellent genotype 3a potency. Methoxy- and ethoxyquinolines
(5l, 5m) were particularly potent, however, in contrast to the
amines, the corresponding ethers generally exhibited excellent cel-
lular potency and rat liver exposure. Increasing the size or com-
plexity of the alkyl group did not generally lead to any further
improvement (5n). However, methylthiazole analog 5o does have
slightly improved gt 3a potency (3 nM) and also offers an improved
gt 1 replicon activity with 50% NHS compared to ethyl analog
5m, as well as improved rat liver exposure compared to methyl
analog 5l.
substitution reactions, we first converted 4 to the corresponding
quinoline-2-triflate (12), and then carried out Suzuki reactions26
(see Supplementary data) with a variety of boronic acids (Table 1).
These were then readily converted into products 5a–5f using stan-
dard conditions. As is readily apparent from table 1, substitution at
the ortho-, meta-, and para-positions (5a–5e) led to either no
improvement or a reduction in gt 3a potency, although similar
rat liver concentrations and replicon potency was generally main-
tained. Changing the simple aryl ring to a heterocycle (5f) also did
not lead to improved gt 3a potency, and instead resulted in the loss
of rat liver exposure.
The triflate 12 can also be readily converted into N-substituted
analogs via simple displacement reactions (Table 1, 5g–5j).27 The
resulting 2-aminoquinolines generally display excellent gt 3a po-
tency, but poor rat liver exposure follow oral dosing. Alkylamine
analogs (5g, 5i, 5j) possessed single digit nanomolar activity versus
gt 3a, but all led to <100 nM rat liver concentrations.
Capping 5g with ethylchloroformate leads to N-methyl-ethylc-
arbamate 5h, which displays a promising profile of 4 nM gt 3a po-
tency, good gt 1 replicon activity and rat liver exposure (42
4 h.
lM) at
Given this excellent profile, we decided to explore other hetero-
cyclic ether analogs, this time with cyclopentyl glycine in P3
(Table 2, 14a–14e). One can see the generally potency enhancing
The excellent potency of amino analogs prompted us to exam-
ine ether derivatives as well. Unfortunately, neither phenols nor

7204
M. T. Rudd et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7201–7206
Table 2
2-Alkoxyquinoline SAR
H
O
O
N
O
O
O
N
O
OR
O
O
CO2Me
O
N
O
N
H
N
H
N
S
HN
N
O
O
O
H
O
O
R1
R1
4 (R1 = Cyclohexyl)
13 (R1 = Cyclopentyl)
5j-5o (R1 = Cyclohexyl)
14a-14e (R1 = Cyclopentyl)
#
OR
1b Ki (nM)a
3a Ki (nM)a
1b replicon IC50 (nM)b
10% FBS 50% NHS
[liver]4h(l
M)c
OH
O
5k
5l
0.07
0.04
0.09
23
85
4
460
19
0.07
5.4
40
4.1
7.6
O
5m
6
43
O
5n
5o
0.05
0.1
15
5
34
16
4.6
19
S
3.1
3.5
O
O
O
O
N
S
14a
14b
14c
0.09
<0.02
0.03
1.6
2
5
26
0.8
N
S
4
26
2.7
N
N
O
N
1.0
36
170
0.03
N
N
14d
14e
<0.02
0.03
1.1
2.2
4
2
16
11
2.6
35
O
O
a
b
c
NS3/4a protease time-resolved fluorescence assay.
Cell-based replicon assay.
5 mg/kg dosed orally in PEG400 (n = 2, rat), liver levels after 4 h.
effect of changing to cyclopentyl glycine by comparing 5o–14a.
Other related heterocyclic analogs (14b–14d) have excellent geno-
type 3a potency, however they uniformly show low to moderate
liver exposure in rat following oral dosing, and generally have poor
to moderate replicon potency in the presence of 50% NHS. The
preferred group within this sub-series appears to be oxazole 14d
which has 1 nM gt 3a potency, good replicon activity, and moder-
O
O
N
O
OTf
O
O
N
O
R
O
CO2Me
O
O
N
N
H
N
H
N
S
O
HN
N
O
O
H
O
O
12
5a-5j
ate rat liver level (2.6 lM). Interestingly, returning to the simple
ethyl ether derivative with the P3 cyclopentyl group led to a com-
pound with the overall optimum profile within the 2-alkoxyquin-
oline series. 14e has excellent gt 1b (0.03 nM) and gt 3a potency
(2 nM) as well as gt 1b replicon activity (2 nM (10% FBS); 11 nM
Scheme 4. Strategy for synthesis of tricyclic P2.
activity (3 nM) and rat liver exposure (27 lM). The effects of sub-
stituents on the top ring of the tricycle were then explored, and
while substitution at the 2-position was not well tolerated (15h)
in terms of gt 3a potency, substitution at the 3-position was gener-
ally somewhat beneficial. C3-methyl analog 15d provided similar
gt 3a potency and rat liver exposure, but was 2-fold more potent
in the 50% NHS replicon assay. Cyano (15e), fluoro (15f), and meth-
oxy (15g) groups all boosted gt 3a potency by ꢀ2-fold to sub-nano-
molar regions, while methoxy analog 15g also provided a slight
increase in rat liver exposure compared to unsubstituted 15c.
In summary, optimization for genotype 3a potency and rapid
screening for rat liver exposure31 (following oral dosing) in the
P2-quinoline series of the P2–P4 macrocyclic HCV NS3/4a protease
inhibitors has led to the discovery of several key structural
features; notably the genotype 3a potency enhancing effects of
various 2-amino and 2-alkoxy quinoline groups, as well as two dif-
ferent types of tricyclic analogs. Within these sub-series, it appears
(50% NHS)) and rat liver exposure (35 lM).
In an effort to further explore the space occupied by 2-amino
and -ethoxy groups, an effort was undertaken to tie back the sub-
stituent into another ring, thus forming a tricyclic P2 group. The
versatility of the triflate intermediate 12 was again exploited
through simple conversion to imidazo-tricycle 15a (Scheme 4).
As Table 3 illustrates, compared to 14e, P2 tricyclic analog 15a
possesses similar gt 3a potency (1.8 nM) however, unfortunately it
has relatively poor replicon potency and rat liver exposure.
Removal of the C7 methoxy group (15b) reduces the gt 3a potency
slightly (5.2 nM) and this compound also suffers from poor repli-
con potency and rat liver exposure. However, given the promising
potency of the imidazo-tricycles, we synthesized the related
isoquinoline-tricycle 15c to further explore P2-tricycle SAR (see
Supplementary data). Gratifyingly, 15c displayed excellent gt 3a
potency (1.7 nM), and, in contrast to 15a, also had good replicon

M. T. Rudd et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7201–7206
7205
Table 3
Tricyclic P2
P2
O
O
O
O
N
H
N
O
S
O
HN
N
O
H
O
R
15a-15g
#
P2
Rd
1b Ki (nM)a
3a Ki (nM)a
1b replicon IC50 (nM)b
10% FBS 50% NHS
[liver]4h (l
M)c
N
O
N
15a
15b
Cyh
Cyh
0.04
0.08
1.8
5.2
43
33
140
180
0.8
0.7
N
N
O
15c
15h
Cyp
Cyp
<0.02
<0.02
1.7
36
3
7
29
31
27
—
N
Cl
O
O
O
O
O
N
Me
CN
F
15d
15e
15f
Cyp
Cyp
Cyp
Cyp
<0.02
<0.02
<0.02
<0.02
1.9
0.8
0.9
0.8
4
4
9
4
15
13
43
27
16
7.5
22
35
N
N
N
N
O
15g
a
NS3/4a protease time-resolved fluorescence assay.
Cell-based replicon assay.
5 mg/kg dosed orally in PEG400 (n = 2, rat), liver levels after 4 h.
b
c
d
Cyh = cyclohexyl; Cyp = cyclopentyl.
Table 4
Compound comparison and gt 1mutant profile
#
1b Ki (nM)a
3a Ki (nM)a
1b replicon IC50 (nM)b
10% FBS 50% NHS
[liver]4h
(l
M)c
gt 1b Ki (nM)a
R155K
A156T
5h
5o
14e
15g
0.03
0.1
0.03
<0.02
4.3
3.1
2.2
0.8
5
3.5
2
27
16
11
27
42
19
35
35
3.3
2.1
1.3
0.4
87
88
41
16
4
a
b
c
NS3/4a protease time-resolved fluorescence assay.
Cell-based replicon assay.
5 mg/kg dosed orally in PEG400 (n = 2), liver levels after 4 h.

7206
M. T. Rudd et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7201–7206
et al Bioorg. Med. Chem. Lett. 2008, 18, 4853. and ITMN-191 (R7227); (c)
Seiwert, S. D.; Andrews, S. W.; Jiang, Y., et al Antimicrob. Agents Chemother.
2008, 52, 4432.
the compounds which offer the best balance between gt 3a
potency, gt 1b replicon activity, and rat liver exposure following
oral dosing are amino-carbamate 5h, quinolinoxymethyl-thiazole
analog 5o, ethoxy derivative 14e, and 3-methoxy substituted iso-
quinoline tricycle 15g. As is shown in Table 4, in addition to excel-
lent gt 1b/3a potency, these analogs also possess excellent potency
versus the gt 1b mutant R155K,32 but lose some activity against gt
1b A156T. Improving potency against this variant will be the
subject of a subsequent publication.33
11. Liverton, N. J.; Holloway, M. K.; McCauley, J. A., et al J. Am. Chem. Soc. 2008, 130,
4607.
12. McCauley, J. A.; McIntyre, C. J.; Rudd, M. T., et al J. Med. Chem. 2010, 53,
2443.
13. Liverton, N. J.; Carroll, S. S.; DiMuzio, J. M., et al Antimicrob. Agents Chemother.
2010, 54, 305.
14. Rudd, M. T.; McCauley, J. A.; Butcher, J. W., et al ACS Med. Chem. Lett. 2011, 2,
207.
15. Harper, S.; McCauley, J. A.; Rudd, M. T., et al ACS Med. Chem. Lett. 2012, 3, 332.
16. Summa, V.; Ludmerer, S. W.; McCauley, J. A., et al Antimicrob. Agents Chemother.
2012, 56, 4161.
17. Lindenbach, B. D.; Rice, C. M. Nature 2005, 436, 933.
18. Reitsema, R. H. Chem. Rev. 1948, 43, 47.
Acknowledgments
We thank Dr. Charles W. Ross, III for high-resolution mass spec-
tra data and Sandor L. Varga for interpretation of NMR spectra.
19. Knierzinger, A.; Wolfbeis, O. S. J. Heterocycl. Chem. 1980, 17, 225.
20. Tagawa, Y.; Kawaoka, T.; Goto, Y. J. Heterocycl. Chem. 1997, 34, 1677.
21. Arasappan, A.; Chen, K. X.; Njoroge, F. G.; Parekh, T. N.; Girijavallabhan, V. J.
Org. Chem. 2002, 67, 3923.
22. Holloway, M. K.; Liverton, N. J.; Ludmerer, S. W.; McCauley, J. A.; Olsen, D. B.;
Rudd, M. T.; Vacca, J. P. (Merck & Co., Inc., USA). PCT Int. Appl. 2006, WO
2006119061.
23. Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275.
24. Lee, C. W.; Grubbs, R. H. J. Org. Chem. 2001, 66, 7155.
25. Available from Strem Chemicals, catalog # 44–0082.
26. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
27. Cacchi, S.; Carangio, A.; Fabrizi, G.; Moro, L.; Pace, P. Syn. Lett. 1997, 12, 1400.
28. Beak, P.; Covington, J. B.; Smith, S. G.; White, J. M.; Zeigler, J. M. J. Org. Chem.
1980, 45, 1354.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.08.
106.
References and notes
29. Hughes, D. L. Organic Reactions 1992, 42, 335.
30. Gonzales, R.; Ramos, M. T.; de la Cuesta, E.; Avendano, C. Heterocycles 1993, 36,
315.
1. WHO. Hepatitis C-Global prevalence (update) Wkly. Epidemiol. Reci 1999, 74,
425.
2. Liang, T. J.; Heller, T. Gastroenterology 2004, 127, S62.
3. Hadziyannis, S. J.; Sette, H.; Morgan, T. R., et al Ann. Intern. Med. 2004, 140, 346.
4. Fried, M. W. Hepatology 2002, 36, S237.
5. Moradpour, D.; Penin, F.; Rice, C. M. Nat. Rev. Microbiol. 2007, 5, 453.
6. Chen, K. X.; Njoroge, F. G. Curr. Opin. Invest. Drugs 2009, 10, 821.
7. Lamarre, D.; Anderson, P. C.; Bailey, M., et al Nature 2003, 426, 186.
8. Perni, R. B.; Almquist, S. J.; Byrn, R. A., et al Antimicrob. Agents Chemother. 2006,
50, 899.
9. Malcolm, B. A.; Liu, R.; Lahser, F., et al Antimicrob. Agents Chemother. 2006, 1013,
50.
10. For examples of other P1-P3 macrocycles see TMC435350: (a) Lin, T.-I.; Lenz,
O.; Fanning, G., et al Antimicrob. Agents Chemother. 2009, 53, 1377; (b)
Raboisson, P.; Herman, De K.; Rosenquist, A.; Nilsson, M.; Salvador-Oden, L.,
31. While liver exposure in other species was not routinly assessed, the predictive
nature of this rat liver screening paradigm for discovering compounds which
provide liver exposure in additional species within the P2–P4 macrocyclic
space has been demonstrated several times (see references for: vaniprevir,9,10
MK-1220,14 and MK-517215,16
)
32. The R155K mutant arises clinically in gt 1a infected patients, but we screened
against the gt 1b mutant such that the same background was utilized in
relation to the main screening genotype 1 subtype. In cases where we have
data for both gt 1a and 1b R155K, the Ki values are similar.
33. Rudd, M. T.; McIntyre, C. J.; Romano, J. J., et al Bioorg. Med. Chem. Lett. 2012.
accepted.