Discovery of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5, 7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5, 6-dihydropyran-2-one (PF-00868554) as a potent and orally available hepatitis C virus polymerase inhibitor

Article abstract of DOI:10.1021/jm8014537

The HCV RNA-dependent RNA polymerase has emerged as one of the key targets for novel anti-HCV therapy development. Herein, we report the optimization of the dihydropyrone series inhibitors to improve compound aqueous solubility and reduce CYP2D6 inhibitio

Full text of DOI:10.1021/jm8014537

J. Med. Chem. 2009, 52, 1255–1258
1255
Discovery of (R)-6-Cyclopentyl-6-(2-(2,6-
diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-
[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-
hydroxy-5,6-dihydropyran-2-one
(PF-00868554) as a Potent and Orally
Available Hepatitis C Virus Polymerase
Inhibitor
Hui Li,* John Tatlock, Angelica Linton, Javier Gonzalez,
Tanya Jewell, Leena Patel, Sarah Ludlum, Matthew Drowns,
Sadayappan V. Rahavendran, Heather Skor, Robert Hunter,
Stephanie T. Shi, Koleen J. Herlihy, Hans Parge,
Michael Hickey, Xiu Yu, Fannie Chau, Jim Nonomiya,† and
Cristina Lewis†
Pfizer Global Research and DeVelopment, La Jolla Laboratories,
10770 Science Center DriVe, San Diego, California 92121
Figure 1. HCV NS5B polymerase inhibitors in clinical trials.
Scheme 1. Synthesis of Carbon-Linked Dihydropyronea
ReceiVed NoVember 18, 2008
Abstract: The HCV RNA-dependent RNA polymerase has emerged
as one of the key targets for novel anti-HCV therapy development.
Herein, we report the optimization of the dihydropyrone series inhibitors
to improve compound aqueous solubility and reduce CYP2D6 inhibi-
tion, which led to the discovery of compound 24 (PF-00868554).
Compound 24 is a potent and selective HCV polymerase inhibitor with
a favorable pharmacokinetic profile and has recently entered a phase
II clinical evaluation in patients with genotype 1 HCV.
a Reagents and conditions: (a) ArBr, Pd(PPh3)2Cl2, CuI, i-Pr2NH, DMF,
90 °C; (b) Pd(OH)2, H2, MeOH, 25 °C; (c) K2CO3, MeOH, 45 °C; (d)
Ar′CHO, MeOH, BH3 ·SMe2, 25 °C.
Hepatitis C virus (HCVa) infects over 3% of the world
population and is one of the leading causes of chronic liver
diseases.1 Currently there is no vaccine available for HCV, and
the standard treatment suffers from both poor response rate (ca.
50%) in patients with genotype 1 and severe side effects.
Therefore, a safer and more effective HCV therapy remains a
significant unmet medical need.2
The HCV genome encodes a poly protein of approximately
3000 amino acids, which is further processed by host peptidases
and viral proteases to provide a series of structural and
nonstructural proteins. Among all viral enzymes, the HCV RNA-
dependent RNA polymerase has been the subject of intense
research in the past decade because of its essential role in viral
replication and distinct nature from human enzymes. A number
of HCV polymerase inhibitors, including both nucleosides,3
compounds 1 (NM-2834), 2 (R-16265), 3 (R-71286), and non-
nucleosides, compound 4 (HCV-7967), VCH-759 (structure not
discloased),8 GS-9190 (structure not disclosed),9 and 5 (GSK-
62543310), have entered human clinical trials and yielded
encouraging results in viral load reduction and patient response
rate (Figure 1). The development of compounds 1, 2, 4, and 5,
however, has been terminated due to significant side effects.
Recently, several additional non-nucleoside inhibitors11-13 and
one nucleoside inhibitor14 were advanced into phase I trials,
followed closely by a number of other agents in preclinical
evaluation. The ongoing challenge for all clinical developments
of these polymerase inhibitors will be in achieving the appropri-
ate balance between improved efficacy and an acceptable safety
profile.
We have identified and optimized a series of dihydropyrones
as HCV polymerase inhibitors that bind to an allosteric site in
the thumb domain of the protein.15 In our previous communica-
tions,16,17 we reported the structure-activity relationship (SAR),
which led to the identification of compound 6, a potent and
selective HCV polymerase inhibitor with favorable pharmaco-
kinetic profiles. During the subsequent scale up effort, however,
a new crystalline form emerged with significantly lower
solubility (ca. 80-fold less). In vivo animal pharmacokinetic
studies later confirmed that this new form of compound 6
displayed significant reduction in exposure levels and bioavail-
ability after oral dosing, which made further development of
this compound unlikely.
In addition to its low aqueous solubility, compound 6 was a
potent inhibitor of the cytochrome P450 isozyme 2D6 (CYP2D6)
with an IC50 of 0.3 µM. Although representing only ap-
proximately 2-4% of the total human liver cytochrome P450
content, CYP2D6 plays a prominent role in the oxidation of
xenobiotics.18 Because most HCV patients are on combination
therapy with other medications and a portion of human
population already has a deficiency in this key metabolism
enzyme due to genetic polymophism, it is highly desirable for
any new anti-HCV therapy to avoid potential complications of
* To whom correspondence should be addressed. Phone: (858)622-6076.
Fax: (877)481-9190. E-mail: hui.li@pfizer.com.
†
Current affiliation: Genentech Inc., 1 DNA Way, South San Francisco,
California 94080.
a Abbreviations: HCV, hepatitis C virus; CYP2D6, cytochrome P450
isozyme 2D6.
10.1021/jm8014537 CCC: $40.75
2009 American Chemical Society
Published on Web 02/11/2009

1256 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 5
Table 1. CYP2D6 Inhibitory Profiles of C-Linked Dihydropyrones
Letters
Table 2. Further Optimization of C-Linked Dihydropyrones
a HCV NS5B ∆21 genotype 1b BK strain.16 b Antiviral activity (EC50)
and cytotoxicity (CC50) were generated in the genotype 1b-con1 reporter
replicon assay.20
drug-drug interactions in clinical development. In this paper,
we report our efforts specifically addressing these two issues
associated with compound 6.
a Genotype 1b. b Percentage remaining after 4 h incubation with human
hepatocytes.
The dihydropyrone was readily synthesized from the acetylene
intermediate 7 as reported previously (Scheme 1).17 A palladium
catalyzed Sonogashira reaction between aromatic bromides and
alkyne 7 provided compound 8 in good yields. Hydrogenation
of the carbon-carbon triple bond in the presence of Pd(OH)2,
followed by a cyclization reaction with K2CO3 in MeOH at 45
°C, yielded the desired dihyropyrone core 9. Introduction of
the right-hand aromatic group was accomplished through a
borane-dimethyl sulfide mediated coupling reaction with
aromatic aldehyde in MeOH.
group of compound 6 with a hydroxyl group completely
eliminated detectable inhibition of CYP2D6 (compound 15,
Table 1).
With all the observations, it became evident that the cyano
group of compound 6 was likely involved in the interaction with
the CYP2D6 enzyme, possibly through hydrogen bond interac-
tions. Removal of such interactions or introduction of steric
hindrance around the cyano group could alleviate the undesirable
drug-drug interaction potential. Modifications in this region
of the molecule were also well tolerated with regard to
compound potency against the HCV polymerase enzyme, which
provided good opportunity for further optimization of HCV
potency and selectivity over CYP2D6.
From previous SAR and X-ray cocrystal structural informa-
tion,16,17 the left portion of the dihydropyrone inhibitors (Ar1
in Table 1) provides key hydrophobic interactions as well as a
direct hydrogen bond interaction between the nitrogen atom from
the cyano group (compound 6) and the Leu-497 backbone NH
in the HCV polymerase protein. In particular, the fluorine at
the 3-position and one of the methyl groups off the 4-position
in compound 6 occupied two small hydrophobic pockets formed
by adjacent amino acid residues, including Leu-419, Met-423,
Val-485, Ala-486, Leu-489, and Leu-497. Further examination
of X-ray cocrystal structure suggested that an ethyl substitution
from the 3-position of the phenyl ring could occupy these two
hydrophobic pockets simultaneously. Indeed, compound 16
(Table 2, IC50 ) 0.01 µM) provided good enzymatic potency
and moderate cell-based replicon activity (EC50 ) 0.59 µM).
Further analogues with this key structural feature were synthe-
Given the importance of CYP2D6 in drug metabolism, several
pharmacophore models have been developed and recently a
crystal structure of human CYP2D6 has also been reported. The
triazolopyrimidine system in compound 6 is only mildly basic
(ACD pKa ∼ 1.5) and not sufficient to make a salt bridge
interaction with acidic residues in the CYP proteins. Indeed,
compound 11, which removed two nitrogen atoms from
compound 6, was still a potent CYP2D6 inhibitor with an IC50
of 0.70 µM. A more structurally distinct analogue 12, containing
a simple 3-methoxyphenyl moiety, also demonstrated potent
CYP2D6 inhibition (IC50 ) 0.77 µM) with much reduced
activity in the cell-based replicon assay19,20 (EC50 ) 2.9 µM)
against HCV (genotype 1b). On the contrary, structural modi-
fications in the Ar1 region had a much more dramatic impact
on their CYP2D6 inhibitory properties. Substitution of a fluorine
atom at the 3-position with a chlorine (compound 13, Table 1)
resulted in a 13-fold reduction in CYP2D6 inhibition (IC50
)
3.9 µM). Alternatively changing from a gem-dimethyl-cyano
group at the 4-position to the corresponding gem-diethyl-cyano
dramatically reduced its potency against CYP2D6 (compound
14, CYP2D6 IC50 > 6 µM). Finally, replacement of the cyano

Letters
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 5 1257
Table 3. Pharmacokinetic Profiles of Enantiomer 24
sized, and their potency against HCV polymerase and metabolic
stability in human hepatocyte are summarized in Table 2.
Substitutions at the 4-phenyl position of Ar3 were well
tolerated. Compound 17, which has a 4-hydroxymethyl group,
achieved a 20-fold potency improvement in the replicon assay
with low metabolic stability (37.1% remaining after 4 h
incubation with human hepatocyte). A cyano replacement of
the hydroxyl group in compound 17 resulted in compound 18,
which showed a comparable EC50 of 0.025 µM with moderate
metabolic stability (54.2% remaining). Introduction of an amide
functionality provided the 4-methylbenzamide analogue 19,
which demonstrated significantly improved stability (85.1%
remaining). However, its replicon potency improved only 3-fold
(EC50) 0.19 µM) as compared to the simple 3-ethylphenyl
analogue 16. Various regioisomers of Et-pyridine as Ar3 group
were also prepared. Substitution of a phenyl ring with a pyridine
not only lowered the overall molecular lipophilicity but also
provided a basic center for aqueous solubility optimization.
While all three isomers showed similar enzymatic potencies with
IC50 below 0.010 µM, their EC50 and metabolic stabilities varied
significantly. The 4-Et-pyridine analogue 20 was slightly more
potent than the corresponding phenyl analogue 16 in the cellular
assay (EC50 of 0.33 µM as compared to 0.59 µM) and its
metabolic stability was fairly poor, with only 33.9% remaining
after hepatocyte incubation. Migration of the ring nitrogen to
3-Et-pyridine (Compound 21, Table 2) achieved an 8-fold
improvement in cell potency (EC50 ) 0.043 µM) and also
increased the compound metabolic stability (77.8% remaining).
The 2-Et-pyridine analogue 22 demonstrated the best metabolic
stability (93.9% remaining) with a slight decrease in replicon
activity (EC50 ) 0.10 µM) compared to the 3-Et-pyridine
analogue 21. Introduction of another ethyl group (compound
23, Table 2) further improved EC50 to 0.067 µM while
maintaining good metabolic stability (84.7% remaining).
species
rat
dog
monkey
NAf
2
po dose (mg/kg)a
iv dose (mg/kg)b
CL (ml/min/kg)c
Vdss (L/kg)d
2
2
2
1
21 ( 4.8
1 ( 0.4
2.5 ( 1
0.94 ( 0.9
75
0.93 ( 0.1
0.25
4.4 ( 1.1
21 ( 5
0.8 ( 0.05
2.1 ( 0.4
NAf
T1/2 (h) terminal
Tmax (h)
1
49
F (%)e
NAf
a IV formulation: 50% PEG 200/10% ethanol/40% water. b PO formula-
tion: 50%PEG200/10% ethanol/40% water. c Total plasma clearance.
d Volume of distribution. e Bioavailability. f Data not available.
Figure 2. Key protein-ligand interactions from X-ray cocrystal
structure of compound 24 in complex with the HCV polymerase 1b-
BK NS5B ∆21 construct.
Compound 23 was further separated into its enantiomers 24
and 25 by chiral HPLC. The two enantiomers exhibited similar
metabolic stability, however, enantiomer 24 was about 8-fold
more potent in the cell-based replicon assay than enantiomer
25.
kg) as well as in rat microsomes (<20 mL/min/kg) closely
correlated with the in vivo clearances (21 ( 4.8 and 21 ( 5
mL/min/kg for rats and monkeys, respectively) (Table 3). The
in vivo pharmacokinetic parameters of compound 24 in
Sprague-Dawley rats, beagle dogs, and cynomolgus monkeys
are summarized in Table 3. In both rats and monkeys, 24 showed
moderate plasma clearance and volume of distribution. In dogs,
however, 24 exhibited both a low plasma clearance (0.93 (
0.1 mL/min/kg) and a low volume of distribution (0.25 L/kg).
The preclinical results suggested that 24 would be amenable
for a twice-daily (BID) dosing regimen.
In summary, we have described the discovery of compound
24 as a potent and selective inhibitor of the HCV polymerase.
Removal of a cyano group from the previous lead molecule
(compound 6) eliminated the undesirable CYP2D6 inhibition,
and introduction of a pyridine aromatic system achieved a good
balance between antiviral potency and favorable pharmacoki-
netic profiles. Compound 24 has recently entered human clinical
trials in patients infected with genotype 1 hepatitis C virus. The
complete characterization of biological activities of this com-
pound is detailed in a separate paper,22 and its clinical outcome
will be published in future communications.
Examination of the X-ray cocrystal structure of compound
24 bound to HCV polymerase21 confirmed key protein-ligand
interactions (Figure 2). As reported previously in cocrystal
structures, binding of dihydropyrone is anchored by the key
hydrophobic interactions between the cyclopentyl group and the
surrounding hydrophobic pocket (Leu-419, Met-423, Tyr-477,
and Trp-528) and the hydrogen bonding network between the
dihydropyrone carbonyl and the donor-donor motif of the
protein (NH from Ser-476 and Tyr-477) through one direct
hydrogen bond and one water-mediated hydrogen bond. The
triazolopyrimidine, connected to the dihydropyrone core through
a methylene linker, formed a π-π stacking interaction with His-
475. Consistent with our previous hypothesis, hydrophobic
interaction between one of the ethyl groups from the pyridine
of compound 24 and the polymerase enzyme provided compa-
rable enzymatic potency in spite of the loss of the direct
hydrogen bond between the Leu-497 residue and the cyano
group of compound 6.
Compound 24 (PF-00868554) was a potent HCV polymerase
inhibitor in both biochemical and cell-based replicon assays and
showed no cytotoxicity up to 320 µM concentration. It did not
inhibit any of the major CYP isoforms (IC50 >30 µM for 1A2,
2C8, 2D6, 3A4, 2C9, and 2C19) and has an aqueous solubility
of 2.55 mg/mL (pH 6.2, free base, crystalline material). The in
vitro hepatic clearance in monkey microsomes (27 mL/min/
Acknowledgment. We thank Drs. Martin Edwards and
Robert Kania for their support and helpful discussion. We also
thank Dr. Natilie Hosea for her contribution in setting up the
CYP2D6 inhibition assay, Chau Doan for her support of the
biochemical assay, and Dr. William Farrell and Christy Au-
rigemma for their assistance in chiral separation.

1258 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 5
Letters
(12) For VCH-222 please see: http://www.virochempharma.com/Research-
and-Development/pipeline/VCH-222.
Supporting Information Available: Experimental procedures
and characterization data for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(13) For ANA598, please see: Rahimy, H. M.; Crowley, A. C.; Freddo,
L. J.; Sergeeva, V. M.; Golec, B. Results of a phase I safety, tolerability
and pharmacokinetic study of ANA598, a non-nucleoside NS5B
polymerase inhibitor, in healthy volunteers. The Liver Meeting, San
Fransisco, October 31-November 4, 2008, Abstract LB 13.
(14) For IDX184, please see: Cretton-Scott, E.; Perigaud, C.; Peyrottes,
S.; Licklider, L.; Camire, M.; Larsson, M.; La Colla, M.; Hildebrand,
E.; Lallos, L.; Bilello, J.; McCarville, J.; Seifer, M.; Liuzzi, M.; Pierra,
C.; Badaroux, E.; Gosselin, G.; Surleraux, D.; Standring, D. N. In
vitro antiviral activity and pharmacology of IDX184, a novel and
potent inhibitor of HCV replication. 43rd Annual Meeting of the
European Association for the Study of the Liver (EASL), Milan, Italy,
April 23-27, 2008.
(15) Love, R. A.; Parge, H. E.; Yu, X.; Hickey, M. J.; Diehl, W.; Gao, J.;
Wriggers, H.; Ekker, A.; Wang, L.; Thomson, J. A.; Dragovich, P. S.;
Fuhrman, S. A. Crystallographic identification of a noncompetitive
inhibitor binding site on the hepatitis C virus NS5B RNA polymerase
enzyme. J. Virol. 2003, 77, 7575–7581.
(16) Li, H.; Tatlock, J.; Linton, A.; Gonzalez, J.; Borchardt, A.; Dragovich,
P.; Jewell, T.; Prins, T.; Zhou, R.; Blazel, J.; Parge, H.; Love, R.;
Hickey, M.; Doan, C.; Shi, S.; Duggal, R.; Lewis, C.; Fuhrman, S.
Identification and structure-based optimization of novel dihydropyrones
as potent HCV RNA polymerase inhibitors. Bioorg. Med. Chem. Lett.
2006, 16, 4834–4838.
References
(1) Sarbah, S. A.; Younossi, Z. M. Hepatitis C: an update on the silent
epidemic. J. Clin. Gastroenterol. 2000, 30, 125–143.
(2) Manns, M. P.; Foster, G. R.; Rockstroh, J. K.; Zeuzem, S.; Zoulim,
F.; Houghton, M. The way forward in HCV treatmentsfinding the
right path. Nat. ReV. Drug DiscoVery 2007, 6, 991–1000.
(3) Carroll, S. S.; Olsen, D. B. Nucleoside analog inhibitors of hepatitis
C virus replication. Infect. Disord.: Drug Targets 2006, 6, 17–29.
(4) Toniutto, P.; Fabris, C.; Bitetto, D.; Fornasiere, E.; Rapetti, R.; Pirisi,
M. Valopicitabine dihydrochloride: a specific polymerase inhibitor of
hepatitis C virus. Curr. Opin. InVest. Drugs 2007, 8, 150–158.
(5) Pockros, P. J.; Nelson, D.; Godofsky, E.; Rodriguez-Torres, M.;
Everson, G. T.; Fried, M. W.; Ghalib, R.; Harrison, S.; Nyberg, L.;
Shiffman, M. L.; Najera, I.; Chan, A.; Hill, G. R1626 plus peginter-
feron Alfa-2a provides potent suppression of hepatitis C virus RNA
and significant antiviral synergy in combination with ribavirin.
Hepatology 2008, 48, 385–397.
(6) Lalezari, J. G., E.; Rodriguez-Torres, M.; DeJesus, E.; Nelson, D.;
Everson, G.; Jacobson, I.; Reddy, R.; Hill, G. Z.; Beard, A.; Symonds,
W. T.; Berrey, M. M.; McHutchison, J. G. Potent antiviral activity of
the HCV nucleoside polymerase inhibitor R7128 with PEG-IFN and
ribavirin: Interim results of R7128 500 mg bid for 28 days., Abstract.
43rd Annual Meeting of the European Association for the Study of
the Liver (EASL), Milan, Italy, April 23-27, 2008.
(7) Chandra, P. R., D.; Harper, D.; Speth, J.; Villano, S.; Bichier, G.
Antiviral Activity of the Non-nucleoside polymerase inhibitor, HCV-
796, in patients with chronic hepatitis C virus: preliminary results from
a randomized, double-blind, placebo-controlled, ascending multiple
dose study. Dig. Dis. Week 2006, Abstract 1.
(8) Cooper, C.; Lawitz, E. J.; Ghali, P.; Rodriguez-Torres, M.; Anderson,
F. H.; Lee, S. S.; Proulx, L. Antiviral activity of the non-nucleoside
polymerase inhibitor, VCH-759, in chronic hepatitis C patients: Results
from a randomized, double-blind, placebo-controlled, scending multiple
dose study. The Liver Meeting, Boston, MA, November 2-6, 2007,
Abstract LB11.
(9) Bavisotto, L.; Wang, C. C.; Jacobson, I. M.; Marcellin, P.; Zeuzem,
S.; Lawitz, E. J.; Lunde, M.; Sereni, P.; O’Brien, C.; Oldach, D. W.;
Rhodes, G. Antiviral, pharmacokinetic and safety data for GS-9190,
a non-nucleoside HCV NS5B polymerase inhibitor, in a phase-1 trial
in HCV genotype 1 infected patients. Hepatology 2007, 46, S1, 255A.
(10) Guidetti, R.; Haigh, D.; Hartley, C. D.; Howes, P. D.; Nerozzi, F.;
Smith, S. A. Preparation of 4-(methoxycarbonyl)pyrrolidine-2-car-
boxylic acid derivatives as hepatitis C virus inhibitors. Patent WO
2006045613 A1, 2006.
(11) For VCH-916, please see: Roulx, L.; Bourgault, B.; Chauret, N.;
Larouche, R.; Tanguay, M.; Thibert, R. Results of a safety, tolerability
and pharmacokinetic phase I study of VCH-916, a novel polymerase
inhibitor for HCV, following single ascending doses in healthy
volunteers. 43rd Annual Meeting of the European Association for the
Study of the Liver (EASL), Milan, Italy, April 23-27, 2008, 2008.
(17) Li, H.; Linton, A.; Tatlock, J.; Gonzalez, J.; Borchardt, A.; Abreo,
M.; Jewell, T.; Patel, L.; Drowns, M.; Ludlum, S.; Goble, M.; Yang,
M.; Blazel, J.; Rahavendran, R.; Skor, H.; Shi, S.; Lewis, C.; Fuhrman,
S. Allosteric inhibitors of hepatitis C polymerase: discovery of potent
and orally bioavailable carbon-linked dihydropyrones. J. Med. Chem.
2007, 50, 3969–3672.
(18) Gardiner, S. J.; Begg, E. J. Pharmacogenetics, drug-metabolizing
enzymes, and clinical practice. Pharmacol. ReV. 2006, 58, 521–590.
(19) Hao, W.; Herlihy, K. J.; Zhang, N. J.; Fuhrman, S. A.; Doan, C.; Patick,
A. K.; Duggal, R. Development of a novel dicistronic reporter-
selectable hepatitis C virus replicon suitable for high-throughput
inhibitor screening. Antimicrob. Agents Chemother. 2007, 51, 95–102.
(20) Shi, S. T.; Herlihy, K. J.; Graham, J. P.; Fuhrman, S. A.; Doan, C.;
Parge, H.; Hickey, M.; Gao, J.; Yu, X.; Chau, F.; Gonzalez, J.; Li,
H.; Lewis, C.; Patick, A. K.; Duggal, R. In vitro resistance study of
AG-021541, a novel nonnucleoside inhibitor of the hepatitis C virus
RNA-dependent RNA polymerase. Antimicrob. Agents Chemother.
2008, 52, 675–683.
(21) The atomic coordinates of HCV polymerase complexed with compound
24 have been deposited in the RCSB Protein Data Bank (PDB code
3FRZ).
(22) Shi, S. T. K. J. H.; Graham, J. P.; Nonomiya, J.; Rahavendran, S. V.;
Skor, H.; Irvine, R.; Binford, S.; Tatlock, J.; Li, H.; Gonzalez, J.;
Linton, A.; Patick, A. K.; Lewis, C. Preclinical Characterization of
PF-00868554, a Potent Non-nucleoside Inhibitor of the Hepatitis C
Virus RNA-Dependent RNA Polymerase. Manuscript submitted.
JM8014537