Discovery of novel urea-based hepatitis C protease inhibitors with high potency against protease-inhibitor-resistant mutants

Article abstract of DOI:10.1021/jm201278q

The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.

Full text of DOI:10.1021/jm201278q

Article
pubs.acs.org/jmc
Discovery of Novel Urea-Based Hepatitis C Protease Inhibitors with
High Potency against Protease-Inhibitor-Resistant Mutants
Wieslaw M. Kazmierski,*,† Robert Hamatake,† Maosheng Duan,*,† Lois L. Wright,† Gary K. Smith,†
Richard L. Jarvest,‡ Jing-Jing Ji,† Joel P. Cooper,† Matthew D. Tallant,† Renae M. Crosby,†
Katrina Creech,† Amy Wang,† Xianfeng Li,§ Suoming Zhang,§ Yong-Kang Zhang,§ Yang Liu,§
Charles Z. Ding,§ Yasheen Zhou,§ Jacob J. Plattner,§ Stephen J. Baker,§ Wei Bu,§ and Liang Liu§
†GlaxoSmithKline, Five Moore Drive, Research Triangle Park, North Carolina 27709, United States
‡GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts, SG1 2NY, U.K.
§Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, California 94303, United States
S
* Supporting Information
ABSTRACT: The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole
1, was identified to be a novel and potent HCV protease inhibitor. We further explored
this motif by synthesizing additional urea-based inhibitors and by characterizing them in
replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12,
were found to be more potent in HCV replicon assays than leading second generation
inhibitors such as danoprevir and TMC-435350. Additionally, following oral
administration, inhibitor 12 was found in rat liver in significantly higher concentrations
than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12
has the combination of anti-HCV and pharmacokinetic properties that warrants further
development of this series.
dosing frequency and improving compliance. Despite the
advances of current therapy, there remains a strong need to
develop additional HCV PIs. In this report we describe our
own effort in this area.
INTRODUCTION
■
Hepatitis C virus (HCV) is a major cause of chronic liver
disease that can lead to cirrhosis, carcinoma, and liver failure.
WHO estimates that 130−170 million people are chronically
infected with HCV, a leading cause of liver transplants.1 As a
result of the very recent approval of first HCV protease
inhibitors (PIs) boceprevir2 and telaprevir,3 the current golden
standard for HCV infection involves a combination therapy of
protease inhibitor, injectable pegylated interferon-α (PEG IFN-
α), and ribavirin. While more effective in patients with
genotype (gt) 1 than the previous interferon + ribavirin only
regimen, it is nonetheless less than ideal therapy because of the
well-known interferon side effects.4
RESULTS AND DISCUSSION
■
We recently published several studies describing design,
synthesis, and biological properties of boron-based novel
HCV protease inhibitors.10−13 These compounds incorporated
cyclic boronates and benzoxaboroles as putative warheads on
position P1 targeting HCV protease catalytic triad Ser139 and
on positions P1′ and P4 to identify opportunistic covalent and
noncovalent interactions of these boron-bearing moieties with
the HCV protease. This effort led us to the discovery of very
potent boron-containing analogues, such as 111 (Figure 2).
Investigation of unpurified product 1 revealed the presence
of dihydroxy 2, a type of product that has been described to
form under oxidative deboronation conditions.14 While 2 was
less potent than 1 in the HCV gt1a replicon assay, it was
equipotent in the HCV gt1b replicon assay and more potent in
the gt1a enzyme assay10−13 (Table 1). The potency of 2
compared well with other advanced HCV protease inhibitors
(Table 1). Moreover, macrocyclic P4-urea HCV PIs offered
Other HCV PIs, ITMN-191 (danoprevir),5 TMC-435350,6
MK-7009 (vaniprevir),7 and BI201335, are in advanced clinical
trials (Figure 1).8 However, new generation inhibitors with
improved potency against HCV-PI mutants could be very
valuable to manage a rapid emergence of HCV resistance
observed for HCV PIs in the clinic.9 Such compounds would
also be important in the future direct acting antivirals (DAA)
based combination therapies, which aim to eliminate the use of
PEG IFN-α and thus have the potential to improve the side
effect profile of anti-HCV therapy, in turn increasing patients’
eligibility and compliance. In addition, owing to their
pharmacokinetic properties, both boceprevir and telaprevir
require significant, multiple daily doses. New PIs supporting
low once-a-day dose would add significant benefit by decreasing
Received: September 25, 2011
Published: April 3, 2012
© 2012 American Chemical Society
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Figure 1. Selected advanced HCV protease inhibitors (PIs).
Figure 2. Evolution of potent P4-benzoxaborole 111 into the current series of P4-urea derivatives.
substantial opportunity for lead optimization and appeared
novel and unexplored in the literature.
not shown). Compounds in Table 1 were generally very potent
in gt1a and gt1b stable replicon assays, with an EC50 (highest to
lowest) spread of ∼60-fold in gt1a values (2 vs 23) and ∼15-
fold spread in gt1b values (15 and 4). The SAR trends were
generally less pronounced for the gt1b, consistent with the
narrower range in EC50 values. Compounds with certain
hydrophobic substituents on the urea moiety were very potent
in particular in the gt1a assay, e.g., dimethyl 4, morpholino 9,
piperidine 12, bicyclic 17, and Me-i-Pr 23. Compounds with
more polar substituents, such as carboxamide 15, carboxylate
16, and sulfone 20, were about 3× to 5× less potent than
unsubstituted 3 in gt1a assay but were essentially equipotent to
the unsubstituted 3 in the gt1b assay. In particular, 4, 10−13,
22−24 were more potent in both stable replicon assays than
the advanced HCV PIs (Table 1).
Compounds were also profiled in the transient replicon gt1b
protease mutant assay (Table 1). Most PIs were more potent in
the transient wt than stable wt assay. Interesting SAR was
observed in the mutant assays. The A156S mutant did not
affect susceptibility to urea analogues, which generally
maintained their subnanomolar potency. Mutants A156T and
A156V somewhat affected susceptibility to urea analogues, with
compound potency decreasing up to 200-fold vs wt. On the
other hand, EC50 values of some analogues were highly shifted
against R155K, D168A, and D168V mutants. Transient
EC50(mutant)/EC50(wt) ratios for compounds 5, 7, 8, 23−26
were similar to ratios observed for clinical/marketed HCV PIs
(<1000-fold across the mutant panel). However, stable replicon
EC50 values for 5, 7, 8, 23−26 were generally superior to the
advanced reference PIs in Table 1.
We set out to further explore this motif by synthesizing a
focused set of urea analogues 3−26 (Table 1). The goal was to
discover novel compounds with superior potency or potency
profile on PI-resistant HCV mutants. To this end, final
compounds were evaluated in the panel of laboratory and
clinical HCV protease mutants A156S, A156T, A156V, D168A,
D168V, and R155K (Table 1).
Structure−Activity Relationships. All final compounds
were tested in a gt1a protease assay, gt1a and gt1b stable
replicon assays, and a panel of transient replicon assays. The
transient replicon allows establishment of a panel of key
protease resistance mutation sequences. In our experience, the
transient replicon assay can be somewhat more sensitive to
inhibitors than the stable replicon but provides important
information about mutation sensitivity to the inhibitor when
compared to the wt gt1b EC50 (Table 1).
In general, urea substitutions resulted in lowering of the
stable replicon EC50 values and improving (decreasing)
EC50(mutant)/EC50(wt) ratios. For example the
EC50(D168V)/EC50(wt) is ∼5600 for unsubstituted urea 3
and ∼1400 for dimethylurea 4. Many (but not all, notably 19)
diverse urea substituents especially shift the stable 1a replicon
potency EC50 values into the subnanomolar range. This
suggests that the NS3/4A enzyme tolerates many substituents,
which therefore can be used as “handles” to modulate PK
properties or to install prodrug moiety. For example, the
piperidine-based 12 had much lower in vivo rat clearance (vide
infra) than the more hydrophilic morpholine-based 9 (PK data
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Table 1. Potencies of Compounds 1−26 and Advanced HCV PIs in gt1a Enzyme Assay and Stable and Transient Replicon
a
Assay
a
n.d.: not determined.
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vaniprevir,15 and danoprevir in the mutant panel. This is
demonstrated by the ratio of TMC-435350 EC50 to EC50 of a
representative compound 12 for each virus: wt, 23×; A156S,
3.5×; A156T, 43×; A156V, 49×; D168A, 5×; D168V, 2×;
R155K, 9×. For danoprevir and compound 12, ratios were as
follows: wt, 5×; A156S, 21×; A156T, 5×; A156V, 1×; D168A,
1×; D168V, 0.3×; R155K, 14×. Taken together, these results
suggest that many compounds in Table 1, especially 4, 9, 12,
17, are some of the most potent HCV protease inhibitors
reported to date. Many of these compounds are more potent
on mutant R155K than danoprevir. Mutant R155K emerged in
the 14-day danoprevir monotherapy study and a 12-week
combination study of danoprevir with peginterferon alfa-2a/
ribavirin.16 In addition to changes on positions 80, 156, and
168, R155K was also detected in all subjects in the 5-day
monotherapy with TMC-435350. Although these mutations
spontaneously returned to the baseline over a period of time,
they reappeared in two patients in the follow-up study with
TMC435/PegIFNa-2a/ribavirin, underscoring the need for
more effective agents.17−19
Table 2. Pharmacokinetics of Compounds 7, 8, and 12 in the
in Vivo Rat Model
compound
7
8
12
PK (Rat, iv, 1 mg/kg)
CL (mL·h−1·kg−1
AUC (h·μg/mL)
)
9618
5462
5004
0.107
0.203
0.268
PK (Rat, po, 5 mg/kg)
AUC (h·μg/mL)
terminal t1/2 (h)
0.0405
2.26
7.6
0.069
0.806
6.8
0.266
1.16
20
% max absorption
% bioavailability (JV)
4.2
4
9.4
Liver Concentration (Rat, po Solution, 5 mg/kg)
AUC (h·μg/mL)
terminal t1/2 (h)
308
8.1
Among the clinical compounds listed in Table 1, telaprevir
has the least variable EC50 profile EC50(mutant)/EC50(wt),
with the range 6−57 (lowest to highest ratio) for these
mutants. This range is significantly wider for both TMC-
435350 (0.3−370) and danoprevir (10−466).
DMPK. Selected inhibitors were evaluated in the in vivo rat
PK model.20 Azetidine 7, difluoroazetidine 8, and piperidine 12
exhibited higher liver clearances (Table 2) in comparison with
the ones reported for TMC-435350 (Cl of 505 and 2300
Inhibitors 4, 7, 8, 9, 12, 17, 23, and 24 were substantially
more potent than telaprevir, TMC-435350, boceprevir,
Figure 3. Reagents and conditions: (a) H2S, ether, 95%; (b) Br2, methanol, −30 °C, 54%; (c) (i) 27, ethanol, reflux; (ii) LiOH, water/
tetrahydrofuran/methanol, 50% two steps; (d) BCl3, AlCl3, acetonitrile, 71%; (e) 29, HATU, DIEA, DMF, 40%; (f) tBuOH, KOtBu, 100 °C, 99%;
(g) 33, HATU, DIEA, dichloromethane, rt, 95%; (h) (i) HCl, dioxane, dichloromethane; (ii) 35, HATU, DIEA, dichloromethane, 88% two steps;
(k) Zhan 1B, DCE, c = 0.01 M, 75 °C, 62%; (l) (i) 32, DIAD, Ph3P, THF; (ii) LiOH, tetrahydrofuran, 61%, two steps; (m) (i) 39, CDI, DMF,
DBU; (ii) HCl, dioxane, 60% two steps; (n) cyclohexylamine, triphosgene, dichloroethane, yield 51%.
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mL·h−1·kg−1 at 2 and 4 mg/kg iv doses, respectively).6,18
Compound 24 was less stable in vitro than 12 and was not
advanced to further in vivo studies. When administered at 5
mg/kg po, the dose-normalized (DN) po AUC values for 7, 8,
and 12 (0.008, 0.014, and 0.053 h·μg·kg·mL−1·mg−1,
respectively) were lower than ones for TMC-435350
(calculated po DNAUC = 0.194 h·μg·kg·mL−1·mg−1 for
reported AUC = 7.740 h·μg/mL at 40 mg/kg dose) and
danoprevir (po DNAUC = 0.317 h·μg·kg·mL−1·mg−1 for AUC
= 9.500 h·μg/mL at 30 mg/kg dose). The bioavailability of
TMC-435350 was 44% at 40 mg/kg dose.5,18 We determined
the concentration of 12 in rat liver at the 5 mg/kg po dose.
Remarkably, 12 exhibited a high t1/2 of 8.1 h in the liver, with
corresponding liver AUC∞ of 308 h·μg/mL and liver/plasma
ratio of 1158. For TMC-435350 the reported liver/plasma ratio
was 32−65 at 40 mg/kg po dose.18 For danoprevir, liver AUC∞
was 90.8 h·μg/mL at 30 mg/kg po dose, corresponding to
liver/plasma ratio of ∼10.5 While different doses and
conditions used in these PK studies complicate comparisons,
the PK data strongly suggest that although 12 is not as
bioavailable as danoprevir or TMC-435350, it is present at
much higher concentration in the liver, the main HCV
reservoir.
Synthesis. Compounds 3−26 were synthesized as described
in Figure 3. Several improvements made to the literature
syntheses of the P2* phenol 32,6,20−22 such as the use of
HATU in step e instead of POCl3 and performing the thiazole
cyclization at higher temperature, resulted in high yield and
purity of 32.
Macrocycle 37 was synthesized in high yield by RCM of bis-
olefin 36 at high dilution in the presence of Zhan 1B catalyst.
Ether 38 was secured from 37 and 32 employing Mitsunobu
conditions. Key intermediate 40 was then obtained from 38
after coupling and deprotection steps and was then used to
produce compounds 3−22. The cyclopropyl-substituted
(instead of isopropyl) analogues 23−26 were synthesized in a
similar manner.
AUTHOR INFORMATION
Corresponding Author
*W.M.K. and M.D. are equally contributing corresponding
authors. For W.M.K.: phone, +919-483-9462; fax, 919-315-
6053, e-mail, wieslaw.m.kazmierski@gsk.com. For M.D.; phone,
+86-21-51163719; e-mail, duanmaosheng@hdbiosciences.com.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank our many GSK, Anacor, Bioduro (China), and
ACME Bioscience (Palo Alto, CA) colleagues who participated
in broader aspects of this program for their expert work and
opinions.
ABBREVIATIONS USED
■
DAA, directly acting antiviral; SAR, structure−activity relation-
ship; IFN, interferon; RCM, ring-closing metathesis; HCV,
hepatitis C virus; PI, protease inhibitor; AUC, Area Under
Curve
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* Supporting Information
Details of PK methods, assays, and synthesis procedures. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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