Structure-activity relationships of 4-hydroxy-4-biaryl-proline acylsulfonamide tripeptides: A series of potent NS3 protease inhibitors for the treatment of hepatitis C virus

Article abstract of DOI:10.1016/j.bmcl.2016.12.013

The design and synthesis of a series of tripeptide acylsulfonamides as potent inhibitors of the HCV NS3/4A serine protease is described. These analogues house a C4 aryl, C4 hydroxy-proline at the S2 position of the tripeptide scaffold. Information relatin

Full text of DOI:10.1016/j.bmcl.2016.12.013

Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Structure-activity relationships of 4-hydroxy-4-biaryl-proline
acylsulfonamide tripeptides: A series of potent NS3 protease inhibitors
for the treatment of hepatitis C virus
a
a
a
b
b
Alan Xiangdong Wang a, , Jie Chen , Qian Zhao , Li-Qiang Sun , Jacques Friborg , Fei Yu ,
Dennis Hernandez b, Andrew C. Good c, Herbert E. Klei c, Ramkumar Rajamani c, Kathy Mosure d,
Jay O. Knipe d, Danshi Li d, Jialong Zhu d, Paul C. Levesque d, Fiona McPhee b, Nicholas A. Meanwell a,
⇑
Paul M. Scola a,
⇑
a Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
b Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
c Department of Computational-Aided Drug Design, Bristol-Myers Squibb Research and Development, Research Parkway, Wallingford, CT 06492, United States
d Global Clinical Research, Bristol-Myers Squibb Research and Development, 5, Research Parkway, Wallingford, CT 06492, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The design and synthesis of a series of tripeptide acylsulfonamides as potent inhibitors of the HCV
NS3/4A serine protease is described. These analogues house a C4 aryl, C4 hydroxy-proline at the S2
position of the tripeptide scaffold. Information relating to structure-activity relationships as well as
the pharmacokinetic and cardiovascular profiles of these analogues is provided.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 4 October 2016
Revised 1 December 2016
Accepted 2 December 2016
Available online xxxx
Keywords:
HCV NS3/4A serine protease inhibitors
Tripeptide acylsulfonamides
C4 aryl, C4 hydroxy-proline
Potent and orally bioavailable
Cardiovascular profiles
Hepatitis C virus (HCV) has emerged as a pathogen posing a
serious threat to public health.1 It is estimated that up to 200 mil-
lion people worldwide are chronically infected with HCV, a five-
fold higher prevalence than HIV-1 infection. A significant fraction
of those infected with HCV develop progressive liver disease which
can lead to cirrhosis and hepatocellular carcinoma. To address this
medical need, we embarked on an extensive research effort that
culminated in the discovery of three direct-acting antiviral drugs,
two of which, the NS5A replication complex inhibitor daclatasvir
and the NS3 protease inhibitor asunaprevir, have been approved
for use in combination for the treatment of HCV, while the third,
the NS5B RNA-dependent, RNA polymerase inhibitor beclabuvir,
is in late-stage clinical trials. These agents each inhibit the function
of an essential viral protein and thereby provide an alternative
option for the treatment of this disease.2
of the cyclopropyl acylsulfonamide moiety in exacting potency
towards the NS3/4A protease complex. This tripeptide acylsulfon-
amide was over 100-fold more active in a cell-based HCV genotype
1b (GT-1b) replicon assay than the corresponding carboxylic acid
1.3,4 Hence, the cyclopropyl acylsulfonamide group provided access
to potent inhibitors of the NS3 protease in a linear, tripeptide series
that obviated the need to employ either P1-P3 macrocyclization or
mechanism-based inhibition to derive potency.3–7 While the
potency of 2 was promising, the pharmacokinetic (PK) profile of
this compound was poor and efforts were directed at optimizing
the ADME and antiviral properties in this chemical series. This
optimization effort has been described in detail and led to the dis-
covery of BMS-605339 (3) as the first compound from this series
that was advanced into clinical studies for the treatment of HCV.
Treatment of HCV GT-1-infected subjects with a single 120 mg oral
dose of BMS-605339 (3) resulted in a ꢀ1.8 log10 reduction in viral
load.7 While there were no overt clinical findings observed in sub-
jects receiving drug, there were sub-clinical observations of signif-
icance. Specifically, mild bradycardia, PR interval prolongation and
junctional escape rhythms were recorded in one healthy volunteer
In our pursuit of HCV NS3 protease inhibitors, compound 2
(Fig. 1) was an early program lead that illustrated the importance
⇑
Corresponding authors.
E-mail address: alan.wang@bms.com (A.X. Wang).
http://dx.doi.org/10.1016/j.bmcl.2016.12.013
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Wang A.X., et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.12.013

2
A.X. Wang et al. / Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
MeO
N
O
MeO
N
1: R = CO2H
O
O
O
O
H
N
H
N
S
R
O
O
O
N
N
N
H
N
S
H
H
N
2: R =
O
O
O
N
O
H
O
O
O
O
3: BMS-605339
Fig. 1. Key structures in the discovery of BMS-605339 (3).
and one HCV-infected subject. Similar cardiovascular effects had
been observed pre-clinically in dogs, but only at drug plasma con-
centrations over 100-fold higher than the clinical exposure. These
data suggested that humans were more sensitive to the cardiovas-
cular (CV) effects of BMS-605339 (3) than preclinical species, and
thereby the clinical development of 3 was halted.7
an EC50 value less than 10 nM, as well as pharmacokinetic param-
eters comparable to the clinical lead BMS-605339 (3). It should be
noted, that Boehringer-Ingelheim has recently described their
efforts on a structurally similar chemical series.10 However, the
rationale and outcome described herein are distinct since our effort
was driven by a need to find chemical space free of the cardiovas-
cular liability associated with BMS-605339 (3).
The clinical findings with BMS-605339 (3) focused our effort on
the discovery of a compound that was free of the CV liabilities
associated with this compound. As previously described, an iso-
lated rabbit Langendorff heart model had been employed to assess
the CV effects of BMS-605339 and analogues thereof. From that
effort, compounds were identified that were free of CV effects by
virtue of relatively small structural modifications in the P2⁄ region
of the molecule and this approach ultimately led to the discovery
of BMS-650032 (4, asunaprevir).8 However, the CV signal in this
chemical series was nonetheless problematic as testing for this lia-
bility was both resource-intensive and low throughput in nature.
Moreover, while singletons could be identified that were free of a
CV signal, clear SARs were not realized in compounds bearing the
parent, P2-proline-C4 aryloxy motif. Herein, we describe an SAR
track that ran parallel to the discovery of asunaprevir wherein a
deep seated structural change at the P2 subsite was explored.5,9
We reasoned that a significant structural modification in this
region of the molecule might provide a chemical series free of
the cardiovascular signal associated with the parent C4-aryloxy-
proline series. The objective of this work, beyond minimizing CV
risk, was to identify a lead with activity in the replicon assay with
As illustrated in the co-crystal structure of asunaprevir (4) with
the HCV NS3/4A protease complex (Fig. 2), the S2 subsite of the
enzyme is expansive and solvent-exposed. We focused attention
on the design of a P2⁄ moiety that connected the aromatic sub-
structure directly to the C4-carbon of the proline, as depicted in
5a. A model of 5a in the binding pocket suggested that the interac-
tions of the C4-phenyl group with the P2⁄ subsite of the enzyme
were favorable, while the requisite interactions between the
tripeptide backbone and the enzyme were maintained. The func-
tionalized proline group of 5a was readily assessable as there
was literature precedent for the face-selective addition of Grignard
reagents to the a-face of C4-ketoprolines to yield the desired stere-
ochemistry inherent to 5a.11,12 In this synthetic approach, the ini-
tial target molecules would incorporate a hydroxyl group in the
form of a proline C4 tertiary alcohol as captured in the structure
of 5a. Since this hydroxyl group was not predicted to have direct
contact with the enzyme, it was viewed as a potential handle with
which to modulate physicochemical properties in this series.
The C4-hydroxy-proline-tripeptide backbone scaffold of the
targeted molecules 5a-y was assembled by the pathways outlined
EF loop
EF loop
O
N
Cl
OH
O
O
O
O
O
O
O
H
N
H
N
S
S
N
N
H
N
H
N
H
N
H
N
O
O
O
O
O
O
O
O
4
5a
: asunaprevir
Fig. 2. (a) X-ray co-crystallographic structure of asunaprevir (4) and HCV NS3/4A protease.13 (b) Model of 5a of the proposed C4-aryl proline series bound to HCV NS3/4A
protease.
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A.X. Wang et al. / Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
3
O
HO
O
HO
O
O
O
S
1) TFA/DCE
O
H
N
N
S
HATU/Hunig's base
OH
H
+
N
H2N
N
2) Boc-TLE-OH
N
H
O
DCM
74%
HATU/Hunig's base
O
O
O
DCM
58%
O
O
6
7
O
HO
O
O
O
O
O
O
S
H
Dess Martin
S
H
N
N
N
N
H
N
H
DCM
89%
N
H
H
O
O
N
O
O
N
O
O
O
O
8
9
O
OH
N
O
O
R
S
H
N
RMgX
N
H
H
1) BuLi, -780C
2) CeCl3
O
O
N
or
ArBr
O
O
10%~40%
5v
: R = 4-biphenyl
Scheme 1. Synthetic route to prepare 4-OH-4-aryl proline acylsulfonamide tripeptide 5.
in Scheme 1. Standard amide coupling of commercially-available
(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic
acid with the P1-P10 element 6 afforded amide 7 in 74% yield.
Deprotection of the Boc moiety using TFA followed by amide
coupling, provided the tripeptidic alcohol 8 in 58% yield over the
2 steps. Oxidation using the Dess-Martin periodinane reagent fur-
nished ketone 9 in good yield. Addition of either commercially-
available Grignard reagents, or organocerium reagents made
in situ by treating aryl bromides with n-butyllithium followed by
trans-metalation with cerium (III) chloride, afforded the desired
tertiary alcohols 5a–y in yields ranging from 10% ꢀ 40%.
intermediate 10 in 72% yield. Addition of commercially-available
4-biphenylmagnesium bromide furnished the alcohol 11 in reason-
able yield. Methylation of 11 with methyl iodide provided the
4-methoxy proline derivative 12 in 77% yield, which was followed
by catalytic hydrogenation to quantitatively remove the Cbz
protecting group. Amide coupling of 13 led to 14 in 91% yield
and subsequent saponification using aqueous LiOH afforded acid
15 in excellent yield. Finally, coupling with the P1-P10 amine 6
furnished the desired product 5z in 65% yield.
The SAR exploration began with a simple, unsubstituted phenyl
ring at the C4 position of proline, represented by 5a, which
demonstrated an IC50 of 140 nM in a GT-1a NS3/4A protease inhi-
bition assay (Table 1). This activity was encouraging since 5a was
27-fold more potent than the corresponding C-4 keto-proline 9
The C4-methoxy proline analogue 5z was prepared through an
alternative route (Scheme 2) that relied upon Swern oxidation of
N-Cbz-4-hydroxy proline methyl ester to provide the ketone
HO
O
OH
O
Ar
Ar
KN(TMS)2
1.8 eq ArMgBr
Swern Oxidation
O
O
O
O
N
Cbz
N
Cbz
MeI/THF/00C
77%
N
Cbz
N
Cbz
PhCH3, 00C to rt
60%
DCM, -780C to rt
72%
O
O
O
O
10
11
12
O
N
O
N
Ar
Ar
O
LiOH
Ar
Boc-TLE-OH
O
O
Pd/C, H2, 25 psi
OH
O
H
N
THF/MeOH/H2O
91%
HATU/DCM
Hunig's base Boc
91%
H
N
N
H
MeOH, 5 h
100%
O
O
Boc
O
O
13
14
15
O
O
O
S
O
O
O
N
O
N
H2
N
H
Ar
S
H
6
N
H
N
H
N
O
O
HATU/DCM
Hunig's base
O
O
65%
5z
: Ar = 4-biphenyl
Scheme 2. Synthetic route to prepare 4-MeO-4-aryl proline acylsulfonamide tripeptide 5z.
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4
A.X. Wang et al. / Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
Table 1
Structure, HCV inhibitory activity and cytotoxicity of 4-hydroxy proline acylsulfonamide tripeptides.
X
Y
O
O
O
H
N
S
N
H
N
H
N
O
O
O
O
5
Compd
3
X
Y
GT1a enzyme inhibition IC50
(l
M)
GT1b replicon EC50
(l
M)
CC50 (lM)
H
0.001
0.012
67.3
O
N
O
5a
5b
OH
OH
0.140
0.190
2.36
2.47
>100
>100
F
5c
OH
0.105
1.47
>100
O
5d
5e
5f
OH
OH
OH
OH
OH
OH
OH
0.057
0.052
0.080
0.076
0.703
0.960
0.101
4.06
3.70
3.66
3.27
8.37
3.40
6.25
>100
>100
>100
>100
>100
>100
>100
F
O
Cl
5g
5h
5i
N
5j
O
N
5k
OH
0.162
3.46
>100
O
5l
OH
OH
0.291
0.134
4.95
7.70
>100
>100
N
O
5m
F
5n
5o
5p
OH
OH
OH
0.568
0.728
0.136
4.24
3.94
2.31
>100
>100
>100
F
F
O
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A.X. Wang et al. / Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
5
Table 1 (continued)
Compd
X
Y
GT1a enzyme inhibition IC50
(
lM)
GT1b replicon EC50
(
lM)
CC50 (lM)
5q
OH
0.080
6.45
>100
9
N/A
OH
OH
3.90
1.50
0.026
70.7
30.5
0.412
N/A
O
5r
5s
>100
88.4
5t
OH
OH
0.127
0.620
1.12
3.21
>100
46.9
N
S
5u
O
5v
OH
0.004
0.026
43.5
5w
OH
OH
0.005
0.002
0.024
0.039
37.2
O
N
5xa
>100
5xb
5xc
OH
OH
0.007
0.002
0.097
0.041
>100
>100
N
N
S
5y
OH
0.050
0.002
0.265
0.009
55.1
36.4
O
5z
OMe
IC50 values represent the means of at least two independent inhibition measurements derived from the HCV NS3/4A GT-1a protease, while EC50 values represent the means of
at least two independent inhibition measurements derived from the HCV GT-1b replicon assay.
(IC50 = 3.9
l
M). Hence, the presence of the phenyl substituent in 5a
more favorable in the biochemical assay (compare the IC50 values
of 5d-g with those of 5b-c). Bulkiness at this position was detri-
mental to potency (5h, 5i), while insertion of more flexible linkers
such as oxygen and methylene between the phenyl ring and the
bulky alkyl moiety retrieved activity (5j, 5k vs. 5h, 5i). The addition
of a second substituent to the aryl ring was not productive as these
analogues failed to significantly enhance potency (5m–p). How-
ever, incorporating two substituents by fusing a second phenyl ring
to the aryl moiety in 5a provided the naphthyl analogue 5s which
resulted in a 5-fold boost in inhibitory potency. An assessment of
the potential binding mode of 5s suggested that the expanded pla-
narity of the P2⁄ substituent functioned to enhance hydrophobic
and electrostatic interactions with Arg155 while also facilitating
desolvation of the binding pocket (Fig. 3). In contrast to the naph-
thyl moiety in 5s, a 2-benzothiazole heterocycle (5t) at this site did
not lead to a gain in potency.14 The reduced potency of 5t com-
pared to 5s, can be explained by the preferred conformation for
the benzothiazole moiety in 5t in which the carbamate moiety of
and the concurrent change in hybridization at C-4 compared to 9,
resulted in a substantial potency gain. Consistent with this obser-
vation, the C4-allyl analogue, 5r was ꢀ10-fold less active
(IC50 = 1.5 lM) than 5a, suggesting the significance of the rigid aro-
matic ring in 5a for enhancing potency. A model of the binding
mode of 5a with the enzyme suggested that the C4-phenyl group
packed against the side chain of Arg155, while the hydrogen-bond
donors and acceptors along the backbone as well as the acylsulfon-
amide functionality made contact with the enzyme in the fashion
previously described. The model also indicated the potential for
further contact points through the addition of substituents to the
phenyl ring of 5a, providing an immediate direction for the next
phase of the study.
The addition of a single substituent to the phenyl ring of 5a was
considered first. Substitution at the para position with methoxy
(5b) and fluoro (5c) did not exert a significant impact on inhibitory
potency, while meta substitution seemed to be only marginally
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6
A.X. Wang et al. / Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
5s
5t
5v
OH
Y
O
O
O
H
N
S
N
H
N
H
N
O
O
O
O
5s:
2-nathphyl
5t: 2-benzothiazole
5v: 4-biphenyl
Fig. 3. Models of 5s, 5t and 5v bound to HCV NS3 protease.
Table 2
Comparative HCV inhibitory activity and rat pharmacokinetic screening results.
Entry
GT1a enzyme
GT1b cell-based replicon
PAMPA nm/s
@pH 5.5/7.4
4 h screen, ID, PO Plasma
AUC ( M-h)/Liver level (lg/g)
Full Rat PK
screen IC50
(l
M)
screen EC50
(lM)
l
5v
5z
0.004
0.002
0.022
0.009
79/211
381/438
0.90/0.128
2.45/195.3
N/A
F = 58%,
AUC = 14.1
lM-h,
Cl = 17.8 mL/min/kg,
1/2 = 4.6 h, PO
24 h Liver = 1.1
795.1 g/g
T
lM
l
3
0.002
0.012
574/178
10.4/64.7
F = 18%,
AUC = 14.1 lM-h,
Cl = 4.4 mL/min/kg,
1/2 = 4.4 h,
PO 24 h Liver = 0.74
528.2 g/g
T
l
M
l
Table 3
Cardiac electrophysiology parameters in isolated rabbit hearts (compounds perfused at 10
l
M).
Compound
Experimental parameters
HR (%)
SNRT (%)
CF (%)
3
10 min
n = 6, 20 min
10 min
n = 4, 20 min
10 min
n = 2, 20 min
10 min
n = 2, 20 min
Vehicle, 10 min
n = 3, 20 min
ꢁ13
6
69 33
360 229
12 13
ꢁ32 13
10
ꢁ3
ꢁ1
2
4
7
6
4
1
1
ꢁ1
5
ꢁ1
ꢁ2
ꢁ4
ꢁ6
ꢁ3
ꢁ1
ꢁ3
2
1
1
1
7
1
3
4
6
4
3
4
2
1
5
5v
2
7
8
7
3
4
2
ꢁ2
27
20
ꢁ4
ꢁ6
1
8
6
6
5z
Vehicle
8
the P3 cap interfaces with the sulfur atom of the heterocycle ring,
thus destabilizing the preferred binding mode (Fig. 3).
linear array. Modeling suggested that positioning a second phenyl
group in the para- position was optimal and the experimental data
were consistent with this hypothesis. For example, the meta-
biphenyl analogue 5u was similar in potency to the parent 5a,
while the corresponding para- isomer 5v provided a 35-fold
increase in potency in the biochemical enzyme assay, and a 90-fold
improved effect in the cell-based HCV GT-1b replicon assay when
compared to the unsubstituted parent. An assessment of the plau-
sible binding modes suggested that the para-biphenyl orients into
The activity of 5s encouraged further consideration of structural
alternatives at P2⁄ and to this end the biphenyl moiety, an impor-
tant and useful building block in several drugs and natural prod-
ucts, was considered.15 The additional flexibility inherent to the
biphenyl motif compared to a naphthyl ring held potential as a
means of further improving affinity for the NS3 protease by virtue
of the expanded conformational binding modes offered by this
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A.X. Wang et al. / Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
7
the hydrophobic pocket beyond the S2 region, while the distal phe-
nyl ring packs optimally against the side chain of Arg155, estab-
lishing both hydrophobic and electrostatic contacts. It is
interesting to note that replacement of the distal phenyl ring with
5- or 6-membered heterocycles (5xa, 5xb, 5xc) maintained the
inhibitory potency toward NS3 protease in the biochemical
enzyme assay, although this effect deteriorated somewhat in the
cell-based replicon assay, perhaps due to permeability issues asso-
ciated with these more polar elements.
The activity of 5v warranted an exploration of its pharmacoki-
netic profile with compound 3 used as a point of reference. Upon
intraduodenal (ID) dosing to rats, 5v showed a 10-fold lower
plasma exposure and 5-fold lower liver levels when compared to
3 (Table 2). With a need to enhance the absorption properties of
this biphenyl series, we considered structural modifications to
reduce polarity and thereby potentially increase permeability. As
noted above, in its bound conformation, the tertiary hydroxyl moi-
ety in 5v is predicted to be devoid of any direct or water-bridged
indirect interactions with the protein but instead projects into sol-
vent. Hence, capping this hydrogen bond donor with a hydropho-
bic moiety, specifically a methyl group, was considered as a
means of reducing the polarity of this chemical series and poten-
tially improving permeability.16
To this end, the C4-biphenyl-C4-methoxy analogue 5z was syn-
thesized with characterization revealing it to be a key compound in
the series. The C4-methoxy group of 5z improved activity over its
hydroxyl counterpart 5v in both the biochemical and replicon
assays (Table 1). The activity gains in the biochemical assay
observed with 5z might be explained by a lowering of the desolva-
tion penalty associated with ligand binding to the enzyme, while
the increase in cell-based replicon activity may be a consequence
of the enhanced permeability of this compound, a notion sup-
ported by the enhanced permeability of 5z compared to 5v in the
parallel artificial membrane permeability assay (PAMPA) assay
(Table 2).
the 20 min perfusion period (Table 3). A similarly favorable CV pro-
file with respect to HR and SNRT was also observed with the C4-
hydroxy analogue 5v. These data suggested that the CV signal
observed with BMS-605339 (3), was mitigated by the structural
changes incorporated into the P2 motif found in 5v and 5z. How-
ever, 5z produced changes to coronary flow that while modest,
were not observed with BMS-605339 (3) or asunaprevir (4). More-
over, given the observation that humans appeared to be more sen-
sitive to the CV effects of 3 than were preclinical species, the
cardiovascular effects of 5z, although mild in the Langendorff rab-
bit preparation, were a cause for some concern. Hence, while 5z
provided to be a compelling compound with respect to its potency
and PK properties, further study of this compound was halted due
to the potential concern around the preclinical CV profile. As a con-
sequence, more detailed preclinical profiling of asunaprevir (4)
became the focus of the program.
In summary, a series of potent, tripeptidic NS3 protease inhibi-
tors incorporating an aryl moiety at C-4 of the P2 proline residue is
described. Structure-activity relationships established in the P2⁄
region of the molecules defined a linear biaryl system as optimal
for potency. Modeling studies assessing plausible binding modes
suggested that the para-biphenyl orients into the hydrophobic
pocket beyond the S2 region, while the distal phenyl ring packs
optimally against the side chain of Arg155, establishing both
hydrophobic and electrostatic contacts. The pharmacokinetic pro-
file of the C4-biaryl, C4 hydroxy lead, 5v, was relatively poor, how-
ever methylation of this hydroxy moiety provided 5z, which had an
enhanced PK profile and likewise improved antiviral activity. This
lead was tested in the isolated heart model, where a slight increase
in coronary flow was observed. Although this finding was modest,
it nonetheless provided a point of differentiation from the program
lead, asunaprevir (4), which was proven free of a CF effect in this
ex vivo assay. While the biaryl series described herein did not pro-
gress to the clinical stage, these findings provide further insight
into potential applications of the C4 proline biaryl series as a P2
functionality when targeting proteases and as a general motif in
considering drug-like functionality.
The simplicity of the optimized P2⁄ functionality in 5z was
attractive and the PK properties of this biphenyl analogue were
assessed. Upon intra-duodenal (ID) dosing of 5z to rats the
observed plasma and liver levels were respectively 3- and 15-fold
higher than that found with 5v (Table 2). The enhanced systemic
exposure of 5z compared to 5v can be attributed to the methoxy
group in the former which distinguishes this matched pair of struc-
tures and is consistent with the in vitro PAMPA permeability pro-
files of these compounds. In a 24 h PK study, administration of 5z
to rats at a dose of 15 mg/kg resulted in good oral bioavailability
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Please cite this article in press as: Wang A.X., et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.12.013