Synthesis and antiviral activity of novel HCV NS3 protease inhibitors with P4 capping groups

Article abstract of DOI:10.1016/j.bmcl.2012.10.075

We have synthesized and evaluated a series of novel HCV NS3 protease inhibitors with various P4 capping groups, which include urea, carbamate, methoxy-carboxamide, cyclic carbamate and amide, pyruvic amide, oxamate, oxalamide and cyanoguanidine. Most of these compounds are remarkably potent, exhibiting single-digit to sub-nanomolar activity in the enzyme assay and cell-based replicon assay. Selected compounds were also evaluated in the protease-inhibitor-resistant mutant transient replicon assay, and they were found to show quite different potency profiles against a panel of HCV protease-inhibitor-resistant mutants.

Full text of DOI:10.1016/j.bmcl.2012.10.075

Bioorganic & Medicinal Chemistry Letters 22 (2012) 7351–7356
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antiviral activity of novel HCV NS3 protease inhibitors
with P4 capping groups
Xianfeng Li a, , Yang Liu a, Yong-Kang Zhang a, Jacob J. Plattner a, Stephen J. Baker a, Wei Bu a, Liang Liu a,
⇑
b
Yasheen Zhou a, Charles Z. Ding a, Suoming Zhang a, Wieslaw M. Kazmierski b, , Robert Hamatake ,
⇑
Maosheng Duan b, Lois L. Wright b, Gary K. Smith b, Richard L. Jarvest c, Jing-Jing Ji b, Joel P. Cooper b,
Matthew D. Tallant b, Renae M. Crosby b, Katrina Creech b, Amy Wang b
a Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA
b GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709, USA
c GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts, SG1 2NY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
We have synthesized and evaluated a series of novel HCV NS3 protease inhibitors with various P4 cap-
ping groups, which include urea, carbamate, methoxy-carboxamide, cyclic carbamate and amide, pyruvic
amide, oxamate, oxalamide and cyanoguanidine. Most of these compounds are remarkably potent, exhib-
iting single-digit to sub-nanomolar activity in the enzyme assay and cell-based replicon assay. Selected
compounds were also evaluated in the protease-inhibitor-resistant mutant transient replicon assay, and
they were found to show quite different potency profiles against a panel of HCV protease-inhibitor-resis-
tant mutants.
Received 7 September 2012
Revised 8 October 2012
Accepted 15 October 2012
Available online 22 October 2012
Keywords:
Hepatitis C virus
HCV NS3
Ó 2012 Elsevier Ltd. All rights reserved.
Protease inhibitor
Antiviral
Hepatitis C virus (HCV) infection is the major cause of chronic
liver disease leading to cirrhosis, carcinoma and liver failure.1 It is
estimated that more than 170 million people worldwide are chron-
ically infected with HCV. As a result of the recent approval of
first-generation HCV protease inhibitors (PIs) boceprevir2 and
telaprevir,3 the current standard of care for HCV infection involves
a combination therapy of protease inhibitor, injectable pegylated
with greater potency against the wild-type and clinically relevant
HCV PI-resistant mutants.
Several second-generation HCV protease inhibitors, ITMN-191
(danoprevir),6 TMC-435350,7 MK-7009 (vaniprevir),8 BI 201335,9
BMS-650032 (asunaprevir),10 are in advanced clinical trials
(Fig. 1).11 Recently we have reported a novel series of P4 urea-based
NS3 protease inhibitors 1 (Fig. 1).12 Compounds in this class were
found to exhibit superior potency or potency profile against
PI-resistant mutants, compared to danoprevir and TMC-435350.12
To expand the SAR and gain greater insight into the design of new
NS3 protease inhibitors, we sought to explore the impact of differ-
ent P4 capping groups on their antiviral activity and physicochem-
ical properties. Particularly, we were interested in those functional
groups that have been unexplored in NS3 protease inhibitors. In this
Letter, we report the synthesis of these NS3 protease inhibitors and
their antiviral activity including potency profile against a panel of
PI-resistant mutants.
The amine 11, an important intermediate towards these P4 substi-
tuted compounds, was prepared according to Scheme 1. The assem-
bly strategy for making 11 is different from our previously described
method.12 The key step involved an aromatic displacement reaction
of heteroaryl chloride 8 with pre-formed hydroxymacrocycle 9.13,14
Heteroaryl chloride 8 was made in six steps from commercially avail-
able 2-bromo-1-cyclopropylethanone 2. Hydroxymacrocycle 9 was
obtained according to literature procedures.15
interferon-a, and the nucleoside ribavirin. While more effective in
patients with genotype (gt) 1 than the previous interferon +
ribavirin only regimen, this therapy is less than ideal because of
the known interferon side effects including neuropsychiatric
events, flu-like symptoms and hematological toxicities.4 In addi-
tion, both boceprevir and telaprevir require significant, multiple
daily doses due to their moderate potency and pharmacokinetic
properties. New PIs supporting low once-a-day dose would add
significant benefit by decreasing dosing frequency and improving
patient compliance. Furthermore, a rapid development of viral
resistance has already been observed for patients treated with
HCV NS3 protease inhibitors.5 Therefore, there has been tremen-
dous interest in the development of more effective therapeutics
⇑
Corresponding authors. Tel.: +1 650 543 7587; fax: +1 650 543 7660 (X.L.);
tel.: +1 919 483 9462/315 6923 (W.M.K.).
E-mail addresses: xli@anacor.com (X. Li), wieslaw.m.kazmierski@gsk.com (W.M.
Kazmierski).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.10.075

7352
X. Li et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7351–7356
N
F
O
N
O
S
O
O
N
O
N
O
S
O
O
O
O
O
H
N
O
O O
O
H
N
O
O
H
N
HN
S
N
H
N
S
O
N
O
H
N
N
N
H
O
O
H
O
N
O
O
O
Vaniprevir
P2*
Danoprevir
TMC-435350
O
R3
HN
S
O
N
Br
N
O
N
O
O
N
O
S
N
O
Cl
P1
P1'
O
O
O
S
O
O
P3
O
O
H
N
H
H
N
N
NH
O
N
S
N
N
O
O
P4
O
O
O
N
H
P2
OH
O
O
O
R1
N
O
N
O
N
H
N
H
H
R2
BI 201335
Asunaprevir
Figure 1. Examples of NS3 protease inhibitors.
1, P4 urea-based inhibitors
O
N
N
N
b
c
a
d
O
HO
Br
O
Cl
S
S
S
5
O
O
O
2
3
4
O
N
N
N
NH
e
f
O
N
O
N
S
S
S
O
Cl
OH
7
6
8
N
N
O
N
O
O
N
S
S
OH
O
h
g
O
O
O
H
N
O
O
N
S
O
O
O
O
O
H
H
N
N
N
N
O
O
N
S
S
H
Boc
N
O
N
N
H
H
H
Boc
O
H2N
O
N
H
9
10
11
Scheme 1. Reagents and conditions: (a) 2-amino-2-thioxoacetate, MeOH, reflux, 1 h, 40%; (b) NaOH, water, overnight, 79%; (c) oxalyl chloride, DCM, 1 h, 100%; (d) 1-(2-
amino-4-methoxy-3-methylphenyl)ethanone, dioxane, overnight, 69%; (e) KOH, pyridine, 110 °C, 3 h, 98%; (f) POCl3, 110 °C, 1 h, 97%; (g) 8, KOtBu, DMSO, 1 h, 51%; (h) 4.0 M
HCl in dioxane, 2 h, 95%.
Scheme 2 shows the preparation of P4 functionalized deriva-
tives 12–25 from intermediate 11. Ureas 12–13 were prepared
by reaction with dimethylcarbamoyl chloride or diethylcarbamoyl
were prepared by coupling with the corresponding a-methyoxy
acid in the presence of HATU and DIEA. The a-methyoxy acids were
made according to the literature.16 Cyclic carbamate 17 was made
chloride, in the presence of base. The
a-methyoxy amides 14–16
by reaction with 2-chloroethyl chloroformate, followed by

X. Li et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7351–7356
7353
OAr
O
O
O
H
N
N
O
S
OAr
N
OAr
O
H
O
b
HN
O
O
O
O
O
O
O
H
N
H
N
N
O
N
S
O
S
O
N
( )n
N
O
N
14, n = 0
15, n = 1
16, n = 2
H
H
O
HN
O
R1
N
O
R2
12, R1 = R2 = CH3
17
13, R1 = R2 = C2H5
a
c
OAr
OAr
OAr
O
O
O
O
O
O
O
O
H
N
H
O
N
H
N
N
O
O
CN
S
N
N
S
O
O
S
N
N
h
d
N
N
H
H
H
O
O
HN
N
O
H2N
NH
18
25
11
g
e
OAr
f
OAr
O
O
O
H
O
O
N
O
O
H
N
N
S
N
O
S
N
H
OAr
O
N
O
R1
HN
O
H
O
HN
O
O
N
O
H
N
R2
O
N
S
O
O
N
H
O
21, R1 = H, R2 = butyl
t-
O
HN
19
22, R1 = H, R2 = cyclohexanyl
23, R1 = R2 = -(CH2)4-
O
O
24, R1 = R2 = -(CH2)5-
20
Scheme 2. Reagents and conditions: (a) dimethylcarbamoyl chloride or diethylcarbamoyl chloride, TEA, DCM, 34–76%; (b)
a-methoxy cyclic carboxylic acid; HATU, DIEA,
DMF, overnight, 50–68%; (c) (i) 2-chloroethyl chloroformate, TEA, DCM, 0 °C to rt, overnight, (ii) NaH, THF, 0 °C to rt, overnight, 38%; (d) (i) 4-chlorobutyryl chloride, TEA,
DCM, 0 °C to rt, overnight, (ii) NaH, THF, 0 °C, overnight, 38%; (e) pyruvic acid, HATU, DIEA, DMF, 15%; (f) ethyl chlorooxoacetate, TEA, DCM, 15%; (g) R1R2NCOCOOH, HATU,
DIEA, DMF, 10–54%; (h) (i) diphenyl N-cyanocarbonimidate, acetonitrile, 70 °C, 2 h, (ii) t-butyl amine, 120 °C, 3 h, 18%.
treatment with sodium hydride in THF.17 Cyclic amide 18 was pre-
pared similarly by reaction of 11 with 4-chlorobutyryl chloride, fol-
lowed by treatment with sodium hydride in THF. Coupling of
amine 11 with pyruvic acid in the presence of HATU and DIEA gave
pyruvic amide 19. Reaction of amine 11 with ethyl chlorooxoace-
tate in the presence of triethylamine afforded oxamate 20. Oxala-
mide derivatives 21–24 were prepared by coupling of 11 with
the corresponding amino 2-oxoacetic acid in the presence of HATU
and DIEA. Finally, cyanoguanidine 25 was synthesized by reaction
of 11 with diphenyl cyanocarbonimidate, followed by treatment
with t-butyl amine.18
The inhibitory activity of compounds 10–25 was evaluated by
FRET NS3/4A 1a protease domain assay.19 The cellular activity
was determined using 1a and 1b HCV replicon assay.20 Representa-
tive compounds were also evaluated in the wild type (wt) and PI-
resistant mutant genotype 1b transient replicon assays.12 Both
enzymatic and cellular data are summarized in Table 1.
As shown in Table 1, ureas 12 and 13 exhibited sub-nanomolar
potency in the enzyme assay and cell-based replicon assay. These
data are consistent with the results obtained from other urea-
based analogues in our previous publication.12 Compared to urea
12 or 13, carbamate 10 was 10-fold less active against NS3 1a en-
zyme, but showed comparable cellular activity in the sub-nanomo-
lar range. The carbamate moiety was reported as a good capping
group by Llinas-Brunet and co-workers,21 and it is currently pres-
ent in advanced protease inhibitors such as danoprevir6 and BI
201335.9 Amine 11 was less potent than urea in both the enzyme
new P4-capping group, and the oxygen atom has the ability to form
hydrogen-bond interactions and may alter physicochemical prop-
erties of resulting inhibitors. These compounds (14–16) were
essentially equipotent in the enzyme assay and replicon assay,
compared to urea 12 or 13. Extending the ring size in this sub-
series (14–16) did not lead to significant change in potency. To
our surprise, cyclization of the carbamate group or the amide
group at the P4 position was found to be detrimental to potency
in both enzymatic and replicon assay. Cyclic carbamate 17 or
amide 18 showed >30-fold less potent in the replicon 1a and 1b
assay, compared to their linear counterpart carbamate 10 or
carboxamides 14–16. Probably, the formation of a constrained
cyclic ring at the N-terminus significantly alters the geometry or
conformation of these inhibitors which leads to reduced binding
and cell permeability. It is also possible that the unsubstituted
NH group attached to the macrocycle is required for binding, since
replacement of the nitrogen by an oxygen atom results in signifi-
cant loss of activity.22 A limited exploration of oxamate/oxalamide
series was also conducted (19–24). The incorporation of a pyruvic
amide in compound 19 resulted in retention in potency, and oxam-
ate 20 was less potent in the enzyme and replicon assay. All of
oxalamides 21–24 exhibited very similar cellular potency in the
sub-nanomolar range. It is interesting to note that oxalamide 23
or 24 without an NH moiety was more potent than 21 and 22
against NS3 protease enzyme. The differential activity of these
compounds contrasts with the results observed in a literature
NS3 inhibitor series,21 where hydrogen bond donors on the P4
capping group were shown to increase enzymatic potency. Finally,
and replicon assay. a-Methoxy carboxamide in 14–16 represents a

7354
X. Li et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7351–7356
Table 1
Potencies of compounds 10–25 in gt1a enzyme assay and stable and transient replicon assays
OAr
O
H
O
O
N
O
N
S
N
R1
R2
H
O
N
Compd
R1R2N–
NS3/4A
1a IC50
(nM)a
Replicon
gt1b transient replicon, EC50 (nM)c,d
EC50 (nM)b
1a
1b
wt
A156S
A156T
A156V
D168A
D168V
R155K
O
O
HN
10
11
12
6.3
1.3
0.5
0.4
0.4
1.0
0.2
0.02
1.0
0.08
1.2
1.9
20
1.5
41
nd
nd
6.0
155
0.5
H2N
O
0.7
0.3
229
14
1660
27
HN
0.03
0.05
0.5
2.0
N
O
HN
13
0.6
0.3
0.2
0.03
0.1
1.0
5.5
19
51
4.0
N
O
O
HN
HN
14
15
1.6
2.0
0.2
0.2
0.2
0.1
nd
nd
nd
20
nd
85
nd
91
nd
nd
44
O
O
0.04
0.3
263
O
O
HN
16
4.0
0.3
0.3
0.05
0.09
13
49
50
234
25
O
17
18
2.5
20
17
14
27
3.5
6.2
107
219
151
646
1820
1349
3020
3981
977
794
N
O
O
42
24
8.7
N
O
HN
19
20
21
0.8
1.0
4.0
0.5
0.6
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
O
O
HN
HN
2.6
0.6
1.2
0.7
O
O
O
HN
O
O
HN
22
6.3
0.5
0.5
nd
nd
nd
nd
nd
nd
nd
HN
O
O
HN
23
24
1.3
1.0
0.4
0.5
0.4
0.4
nd
nd
nd
nd
nd
49
nd
nd
14
N
O
O
HN
0.02
0.1
5.5
6.2
151
N
O
CN
N
25
2.5
2.5
0.7
0.3
0.5
27
78
331
832
123
HN
NH

X. Li et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7351–7356
7355
Table 1 (continued)
Compd
R1R2N–
NS3/4A
1a IC50
(nM)a
Replicon
gt1b transient replicon, EC50 (nM)c,d
EC50 (nM)b
1a
1b
wt
A156S
A156T
A156V
D168A
D168V
R155K
Telaprevir
TMC-435350
Danoprevir
500
10
0.7
540
2
2
372
1
1.5
34
1
0.2
883
0.3
2
1136
86
10
1965
344
8
638
149
39
207
140
26
1778
56
82
a
b
c
FRET assay with HCV NS3 1a protease domain, as described in Ref. 19.
Replicon assay performed as described in Ref. 20.
gt1b transient replicon assay performed as described in Ref. 12.
nd: not determined.
d
cyanoguanidine 25 showed slightly reduced activity in the enzyme
assay and replicon essay, compared to urea 12 or 13.
amide, cyclic carbamide and amide, pyruvic amide, oxamate, oxala-
mide and cyanoguanidine. According to our SAR investigation, most
of these compounds were remarkably potent and exhibited single-
digit to sub-nanomolar activity in the enzymatic assay and cell-
based replicon assay. Variation of P4-substitution does not seem
to significantly impact the antiviral activity (except for cyclic carba-
mate and amide). This suggests that the NS3/4A enzyme tolerates
many P4 substituents, which therefore can be further used to mod-
ulate drug properties. Furthermore, these potent inhibitors with
different P4 capping groups were found to show different potency
profiles against a panel of HCV PI-resistant mutants. In particular,
ureas 12 and 13 were quite potent on all the PI-resistant mutants
in Table 1, and as such this motif was additionally explored leading
to compounds with exciting anti-HCV activity profile.12
The PI-resistant mutant transient replicon assay provides
important information on mutation sensitivity to the inhibitor,
and inhibitory activity against mutants may offer additional
advantage for sufficient coverage of all relevant NS3 PI-resistant
mutants. Although many compounds with different P4 capping
groups were equipotent in the cell-based assay, they exhibited
quite different potency profile against a panel of HCV PI-resistant
mutants. As shown in Table 1, carbamate 10 and ureas 12–13
exhibited much better potency profile compared to amine 11.
a-Methoxy amide 15 or 16 was equipotent in the stable replicon
assay compared to urea, but they were less active against the panel
of PI-resistant mutants (especially A156T, A156V, R155K). Again,
cyclic carbamate 17 or amide 18 was much less potent against
the panel of PI-resistant mutants, compared to their linear counter-
parts. Cyanoguanidine 25 was much less active against PI-resistant
mutants than urea 12 or 13. On the other hand, oxalamide 24
showed comparable potency profile against the panel of PI-
resistant mutants, which warrants further optimization.
Selected compounds were evaluated in the in vivo rat PK model.
Representative PK data for compounds 10, 13 and 15 are shown in
Table 2. In general, these inhibitors showed high plasma clearance
and low oral exposure in rats. Carbamate 10 showed a 3-fold lower
clearance and thus 3-fold higher rat exposure, compared to urea
13. Urea 13 and methoxy carboxamide 15 exhibited similar plasma
clearance and exposure. These results provide a basis for further
optimization of these potent inhibitors to achieve desirable physi-
cochemical properties and favorable liver concentration following
oral administration.
References and notes
1. (a) De Francesco, R.; Migliaccio, G. Nature 2005, 436, 953; (b) Brown, R. S.
Nature 2005, 436, 973; (c) Alter, M. J. World J. Gastroenterol. 2007, 13, 2436.
2. Njoroge, F. G.; Chen, K. X.; Shih, N. Y.; Piwinski, J. J. Acc. Chem. Res. 2008, 41, 50.
3. Lin, C.; Kwong, A. D.; Perni, R. B. Infect. Disord. Drug Targets 2006, 6, 3.
4. Pearlman, B. L. Am. J. Med. 2004, 117, 344.
5. Rong, L.; Dahari, H.; Ribeiro, R. M.; Perelson, A. S. Sci. Transl. Med. 2010, 2, 30–
32.
6. Seiwert, S. D.; Andrews, S. W.; Jiang, Y.; Serebryany, V.; Tan, H.; Kossen, K.;
Rajagopalan, P. T.; Misialek, S.; Stevens, S. K.; Stoycheva, A.; Hong, J.; Lim, S. R.;
Qin, X.; Rieger, R.; Condroski, K. R.; Zhang, H.; Do, M. G.; Lemieux, C.; Hingorani,
G. P.; Hartley, D. P.; Josey, J. A.; Pan, L.; Beigelman, L.; Blatt, L. M. Antimicrob.
Agents Chemother. 2008, 52, 4432.
7. Raboisson, P.; de Kock, H.; Rosenquist, A.; Nilsson, M.; Salvador-Oden, L.; Lin, T.
I.; Roue, N.; Ivanov, V.; Wähling, H.; Wickström, K.; Hamelink, E.; Edlund, M.;
Vrang, L.; Vendeville, S.; Van de Vreken, W.; McGowan, D.; Tahri, A.; Hu, L.;
Boutton, C.; Lenz, O.; Delouvroy, F.; Pille, G.; Surleraux, D.; Wigerinck, P.;
Samuelsson, B.; Simmen, K. Bioorg. Med. Chem. Lett. 2008, 18, 4853.
8. McCauley, J. A.; McIntyre, C. J.; Rudd, M. T.; Nguyen, K. T.; Romano, J. J.; Butcher,
J. W.; Gilbert, K. F.; Bush, K. J.; Holloway, M. K.; Swestock, J.; Wan, B. L.; Carroll,
S. S.; Dimuzio, J. M.; Graham, D. J.; Ludmerer, S. W.; Mao, S. S.; Stahlhut, M. W.;
Fandozzi, C. M.; Trainor, N.; Olsen, D. B.; Vacca, J. P.; Liverton, N. J. J. Med. Chem.
2010, 53, 2443.
In summary, we described the synthesis and antiviral activity of
a novel series of HCV NS3/4A protease inhibitors with various P4
capping groups, which include urea, carbamate, methoxy-carbox-
9. Bordeleau, J.; Bos, M.; Bousquet, Y.; Cordingley, M. G.; Duan, J.; Forgione, P.;
Garneau, M.; Ghiro, E.; Gorys, V.; Goulet, S.; Halmos, T.; Kawai, S. H.; Naud, J.;
Poupart, M.-A.; White, P. W. J. Med. Chem. 2010, 53, 6466.
10. Pasquinelli, C.; McPhee, F.; Eley, T.; Villegas, C.; Sandy, K.; Sheridan, P.; Persson,
A.; Huang, S.-P.; Hernandez, D.; Sheaffer, A. K.; Scola, P.; Marbury, T.; Lawitz, E.;
Goldwater, R.; Rodriguez-Torres, M.; DeMicco, M.; Wright, D.; Charlton, M.;
Kraft, W. K.; Lopez-Talavera, J.-C.; Grasela, D. M. Antimicrob. Agents Chemother.
1838, 2012, 56.
Table 2
PK parameters of selected inhibitors in male Sprague–Dawley ratsa
Compounds
10
13
15
11. For a recent review on HCV NS3/4A protease inhibitors, see: (a) Flisiak, R.;
Parfieniuk, A. Expert Opin. Investig. Drugs 2010, 19, 63; (b) Kwong, A. D.; McNair,
L.; Jacobson, I.; George, S. Curr. Opin. Pharmacol. 2008, 8, 522; (c) Chen, K. X.;
Njoroge, F. G. Curr. Opin. Investig. Drugs 2009, 10, 821; (d) Reiser, M.; Timm, J.
Expert Rev. Anti Infect. Ther. 2009, 7, 537.
12. Kazmierski, W. M.; Hamatake, R.; Duan, M.; Wright, L. L.; Smith, G. K.; Jarvest,
R. L.; Ji, J.-J.; Cooper, J. P.; Tallant, M. D.; Crosby, R. M.; Creech, K.; Li, X.; Zhang,
S.; Zhang, Y.-K.; Liu, Y.; Ding, C. Z.; Zhou, Y.; Plattner, J. J.; Baker, S. J.; Bu, W.;
Liu, L. J. Med. Chem. 2012, 55, 3021.
13. Seiwert, S. D.; Beigelman, L.; Buckman, B.; Stoycheva, A. D.; Porter, S. B.;
Bradford, W. Z.; Serebryany, V. US 20090269305.
14. Ding, C. Z.; Zhang, Y.-K.; Li, X.; Liu, Y.; Zhang, S.; Zhou, Y.; Plattner, J. J.; Baker, S.
J.; Liu, L.; Duan, M.; Jarvest, R. L.; Ji, J.; Kazmierski, W. M.; Tallant, M. D.; Wright,
L. L.; Smith, G. K.; Crosby, R. M.; Wang, A. A.; Ni, Z.-J.; Zou, W.; Wright, J. Bioorg.
Med. Chem. Lett. 2010, 20, 7317.
CL (mL/h/kg), iv
AUC (h g/mL), iv
AUC0–inf (h g/mL), po
Terminal t1/2 (h)
%Absorptionb
%Fc
2736
0.381
0.201
1.63
14.5
10.0
9093
0.127
0.0487
1.40
19
8635
0.117
0.0491
0.99
16.5
8.2
l
l
7.4
a
Compounds 13 and 15 were dosed orally at a dose of 5 mg/kg (n = 3) and
intravenously at a dose of 1 mg/kg (n = 3), and compound 10 was dosed orally at a
dose of 6.15 mg/kg (n = 3) and intravenously at a dose of 1.23 mg/kg (n = 3).
Calculated from portal vein drug concentrations after oral administration as
compared to that after IV administration.
b
c
Calculated from jugular vein drug concentrations after oral administration as
compared to that after IV administration.

7356
X. Li et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7351–7356
15. (a) McPhee, F.; Campbell, J. A.; Li, W.; D’Andrea, S.; Zheng, Z.; Barbara, G.;
Andrew, C.; Carini, D. J.; Johnson, B. L.; Scola, P. M. WO 2004094452.; (b) Blatt,
L. M.; Wenglowsky, S. M.; Andrews, S. W.; Jiang, Y.; Kennedy, A. L.; Condroski,
K. R.; Josey, J. A.; Stengel, P. J.; Madduru, M. R.; Doherty, G. A.; Woodard, B. T.
WO 2005037214.
16. a) Zhu, H. Y.; Cooper, A. B.; Desai, J. A.; Wang, J. J.-S.; Rane, D. F.; Doll, R. J.;
Njoroge, F. G.; Viyyoor, M. WO 2005014577.; b) Stenstrom, Y.; Koziol, A. E.;
Palenik, G. J.; Jones, W. M. Organometallics 1987, 6, 2079.
19. Li, X.; Zhang, S.; Zhang, Y. K.; Liu, Y.; Ding, C. Z.; Zhou, Y.; Plattner, J. J.; Baker, S.
J.; Bu, W.; Liu, L.; Kazmierski, W. M.; Duan, M.; Grimes, R. M.; Wright, L. L.;
Smith, G. K.; Jarvest, R. L.; Ji, J. J.; Cooper, J. P.; Tallant, M. D.; Crosby, R. M.;
Creech, K.; Ni, Z. J.; Zou, W.; Wright, J. Bioorg. Med. Chem. Lett. 2011, 21, 2048.
20. Lohmann, V.; Korner, F.; Koch, J.-O.; Herian, U.; Theilman, L.; Batenschlager, R.
Science 1999, 285, 110.
21. Llinas-Brunet, M.; Bailey, M. D.; Ghiro, E.; Gorys, V.; Halmos, T.; Poirier, M.;
Rancourt, J.; Goudreau, N. J. Med. Chem. 2004, 47, 6584.
17. Palani, A.; Huang, X.; Xiao, D.; Paliwal, S.; Tsui, H.-C.; Wrobleski, M. L.; Rao, A.
U.; Wang, C.; Shah, S. S.; Shih, N.-Y. WO 2006007540.
18. Lloyd, J.; Jeon, Y. T.; Finlay, H.; Yan, L.; Gross, M. F.; Beaudoin, S. WO
2003063797.
22. Duan, M.; Kazmierski, W.; Crosby, R.; Gartland, M.; Ji, J.; Tallant, M.; Wang, A.;
Hamatake, R.; Wright, L.; Wu, M.; Zhang, Y.-K.; Ding, C. Z.; Li, X.; Liu, Y.; Zhang,
S.; Zhou, Y.; Plattner, J. J.; Baker, S. J. Bioorg. Med. Chem. Lett. 2012, 22, 2993.