P3-P4 ureas and reverse carbamates as potent HCV NS3 protease inhibitors: Effective transposition of the P4 hydrogen bond donor

Article abstract of DOI:10.1016/j.bmcl.2018.04.009

A series of tripeptidic acylsulfonamide inhibitors of HCV NS3 protease were prepared that explored structure-activity relationships (SARs) at the P4 position, and their in vitro and in vivo properties were evaluated. Enhanced potency was observed in a ser

Full text of DOI:10.1016/j.bmcl.2018.04.009

Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
P3-P4 ureas and reverse carbamates as potent HCV NS3 protease
inhibitors: Effective transposition of the P4 hydrogen bond donor
⇑
Brian L. Venables , Ny Sin, Alan Xiangdong Wang, Li-Qiang Sun, Yong Tu, Dennis Hernandez, Amy Sheaffer,
Min Lee, Cindy Dunaj, Guangzhi Zhai, Diana Barry, Jacques Friborg, Fei Yu, Jay Knipe, Jason Sandquist,
Paul Falk, Dawn Parker, Andrew C. Good, Ramkumar Rajamani, Fiona McPhee, Nicholas A. Meanwell,
Paul M. Scola
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:
A series of tripeptidic acylsulfonamide inhibitors of HCV NS3 protease were prepared that explored struc-
ture-activity relationships (SARs) at the P4 position, and their in vitro and in vivo properties were evalu-
ated. Enhanced potency was observed in a series of P4 ureas; however, the PK profiles of these analogues
were less than optimal. In an effort to overcome the PK shortcomings, modifications to the P3-P4 junction
were made. This included a strategy in which one of the two urea N–H groups was either N-methylated or
replaced with an oxygen atom. The former approach provided a series of regioisomeric N-methylated
ureas while the latter gave rise to P4 reverse carbamates, both of which retained potent NS3 inhibitory
properties while relying upon an alternative H-bond donor topology. Details of the SARs and PK profiles
of these analogues are provided.
Received 31 December 2017
Revised 2 April 2018
Accepted 4 April 2018
Available online xxxx
Keywords:
HCV NS3
Inhibitors
Hepatitis C
Protease
Ó 2018 Published by Elsevier Ltd.
Approximately 185 million people worldwide are estimated to
be infected with hepatitis C virus (HCV), a small, enveloped, posi-
tive strand RNA virus.1,2 HCV is a major cause of chronic liver dis-
eases such as cirrhosis and hepatocellular carcinoma.3 Moreover, in
the U.S., this virus has been the leading cause of liver transplant.
was suspended due to a cardiovascular (CV) signal observed in
patients receiving the drug. The CV liability associated with 1
was resolved in the discovery process that ultimately provided
asunaprevir (2, Fig. 1).9 The combination regimen of asunaprevir
with the NS5A inhibitor daclatasvir (3, Fig. 1) was approved in
Japan in July of 2014 for the treatment of patients with genotype
(GT) 1b HCV infection.10
In the course of studies leading to the discovery of 2, modifica-
tions at the P3-P4 interface of these tripeptide-based inhibitors
were examined with the goal of improving potency while main-
taining a PK profile similar to 1.11 In this report, we summarize
those studies which led to the identification of a series of regioiso-
meric N-methylated ureas and P4 reverse carbamates that exhib-
ited potent inhibition against the NS3 protease while relying
upon an alternative H-bond donor topology to that in 1 and 2. In
addition, we summarize efforts to optimize the antiviral activity
in this urea series while also exploring structural modifications
of this functionality designed to optimize the PK properties.
Replacement of the tert-butyl carbamate endcap in 1 with a tert-
butyl urea afforded 4 (Fig. 1), a compound with inhibitory poten-
cies comparable to 1 against enzyme representing HCV NS3 GT
1a and against a HCV GT 1b replicon (Table 1). Urea 4 also demon-
strated a 3-fold improvement in potency against NS3 protease
enzymes representing GT 2b and GT 3a relative to carbamate 1.
The early standard of care, a combination of peg-interferon-
a
and ribavirin, was an important milestone in patient care. How-
ever, this approach ultimately proved only moderately effective
in treating the disease and was associated with side effects, some
of which were significant and prompted discontinuation of treat-
ment.4–6
In an effort to provide interferon-free therapy, drug discovery
efforts have been focused on the procurement of a direct-acting
antiviral cocktail. Toward this end, small molecule discovery pro-
grams targeting the essential viral proteins NS3 protease, NS5A
and NS5B have been studied extensively.7 Our efforts in the NS3
protease arena led to the discovery of a potent series of acyl sulfon-
amide-based tripeptidic inhibitors.8 BMS-605339 (1, Fig. 1)
advanced to the clinic and demonstrated a significant antiviral
response with a 1.8 log10 reduction in viral load after a single,
120 mg dose. However, further development of this compound
⇑
Corresponding author.
E-mail address: brian.venables@bms.com (B.L. Venables).
https://doi.org/10.1016/j.bmcl.2018.04.009
0960-894X/Ó 2018 Published by Elsevier Ltd.
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2
B.L. Venables et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
Fig. 1. BMS-605339 (1), BMS-650032 asunaprevir (2), daclatasvir (3) and compound 4.
Table 1
Structure, NS3 protease enzyme inhibition, HCV replicon cell-based inhibition, and solubility of various P3-P4 derivatives.
Compound
R
GT 1aa NS3/4a
IC50 (nM)
GT 1bb NS3/4a
EC50 (nM)
Solubility @
pH = 6.5
(mg/mL)
GT 2ba NS3/4a
IC50 (nM)
GT 3aa NS3/4a
IC50 (nM)
Rat Screenc
Plasma AUC
(ng h/mL)
Rat Screenc Liver
Exposure @ 4 h
(ng/g)
1
2.1
0.7
3.5
12
11
79
0.001
187
59
95
7423
64,708
4
0.013
34
497
1110
7a
327
433
7b
8a
8b
0.46
0.82
0.22
31
17
7.9
33
71
114
42
158
81
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B.L. Venables et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
3
Table 1 (continued)
Compound
R
GT 1aa NS3/4a
IC50 (nM)
GT 1bb NS3/4a
EC50 (nM)
Solubility @
pH = 6.5
(mg/mL)
GT 2ba NS3/4a
IC50 (nM)
GT 3aa NS3/4a
IC50 (nM)
Rat Screenc
Plasma AUC
(ng h/mL)
Rat Screenc Liver
Exposure @ 4 h
(ng/g)
9a
23
910
9b
0.90
71
10
11
2.5
2
56
70
1.07
172
121
170
171
0.500
12
13
0.44
0.40
24
12
0.570
0.326
31
17
60
72
14
15
0.30
1.2
11
31
0.609
0.225
14
66
26
3275
838
201
16
17
2.6
4.7
73
0.259
0.134
184
226
524
265
176
18
19
20
21
22
23
0.34
0.19
0.050
0.24
0.21
0.27
17
10
54
61
40
34
0.754
0.001
>1.16
0.557
0.095
0.132
19
59
9
41
93
11
16
15
18
632
91
4849
0
14
23
19
1631
87
a
b
c
GT 1a = genotype 1a; GT 2b = genotype 2b; GT 3a = genotype 3a; HCV NS3 enzyme inhibitory activity was assessed according to the conditions described in Ref 13.
GT 1b = genotype 1b; HCV replicon activity was assessed in the presence of 10% fetal bovine serum (FBS) according to the conditions described in Ref 13.
Intraduodenal (ID) single dose, 15 mg/kg, n = 2, endpoint = 4 h using conditions described in Ref. 9a.
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B.L. Venables et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
Computational modeling of 4 bound to a NS3/4A protease complex
suggested that the urea motif of ligand 4 could participate in a
bidentate hydrogen-bonding interaction with the backbone car-
bonyl of Ala-157, as depicted in Fig. 2.12 Additionally, 4 demon-
strated a 10-fold improvement in aqueous solubility relative to
its carbamate counterpart 1.
Based on its promising in vitro antiviral activity, the pharma-
cokinetic (PK) profile of 4 in the rat was examined. This compound
was administrated via intraduodenal dosing and exposure levels in
the plasma and liver were measured over a 4 h period. The concen-
tration of 4 in both plasma and liver was found to be significantly
lower than the levels observed after dosing 1 under the same pro-
tocol (Table 2). Despite the inferior PK profile of 4 compared to 1,
the exploration of P4 urea caps remained of interest given the
enhanced potency toward NS3 protease enzymes representing GT
1a, GT 2b and GT 3a.
Fig. 2. Compound 4 modeled into the HCV NS3/4A protease GT1a binding site.
Table 2
Transpositioning of the P3-P4 hydrogen-bond donor.
Compound P2*
GT1aa NS3/4a
IC50 (nM)
GT1bb NS3/4a
EC50 (nM)
GT2ba NS3/4a
IC50 (nM)
GT3aa NS3/4a
IC50 (nM)
Rat Screenc Plasma
AUC (ng h/mL)
Rat Screenc Liver
Exposure @ 4 h (ng/g)
24
25
26
27
1
1
1
1
4.5
6.0
10
18
18
7.4
16
17
61
17
7850
72
4.6
8.0
2.3
7.0
3.2
8.7
9.2
100
32
2602
28
1
945
NDd
29
30
31
1
1
2
35
2.8
10
66
NDd
16
1243
1776
81
243
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B.L. Venables et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
5
Table 2 (continued)
Compound P2*
GT1aa NS3/4a
IC50 (nM)
GT1bb NS3/4a
EC50 (nM)
GT2ba NS3/4a
IC50 (nM)
GT3aa NS3/4a
IC50 (nM)
Rat Screenc Plasma
AUC (ng h/mL)
Rat Screenc Liver
Exposure @ 4 h (ng/g)
32
2
1.7
129
33
34
35
1
1
1
13
11
12
42
30
85
82
3772
3431
430
277
843
95
NDd
a
b
c
GT 1a = genotype 1a; GT 2b = genotype 2b; GT 3a = genotype 3a; HCV NS3 enzyme inhibitory activity was assessed according to the conditions described in Ref. 13.
GT 1b = genotype 1b; HCV replicon activity was assessed in the presence of 10% fetal bovine serum (FBS) according to the conditions described in Ref. 13.
Intraduodenal (ID) single dose, 15 mg/kg, n = 2, endpoint = 4 h using conditions described in Ref. 9a.
ND = not detected.
d
Fig. 3. Synthesis of P3-P4 ureas 7–19 and P4-P5 amides 21–23. Reagents and conditions: a) 50% TFA in CH2Cl2, RT, quantitative; b) 1 M HCl in Et2O, RT, 88%; c) N,N0-
disuccinimidyl carbonate, DIPEA, THF, 70 °C, 30 min; d) R1R2NH, THF, RT, 18 h, 20–82% yield from 5; e) 50% TFA in DCM, RT, 96% yield; f) R1R2NH, HATU, N-methylmorpholine,
DCM, RT, 18 h, 39–81% yield.
A general synthesis of P3-P4 ureas was devised and is depicted
in Fig. 3. N-Boc deprotection of 1 with TFA in CH2Cl2 followed by
conversion to the hydrochloride salt provided amine 5 as a powder
isolable by simple filtration. Treatment of 5 with N,N’-disuccin-
imidyl carbonate afforded a mixture of the succinimidyl carbonate
6a and isocyanate 6b. The crude mixture was treated directly with
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B.L. Venables et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
excess amine to provide the desired ureas 7–19 in good overall
yield. A series of P4-P5 amides was prepared via hydrolysis of
the tert-butyl ester in 19 followed by subsequent HATU-mediated
coupling of the resultant acid 20 with various amines to give the
series of amides 21–23.
All compounds were testedfor enzymeinhibitory activitytoward
a homogeneous full-length HCV GT 1a NS3/4A protease complex
with the more active molecules additionally tested against NS3/4A
complexes representing GT 2b and 3a proteases.9b,13 Activity was
assessed using a fluorescence resonance energy transfer (FRET)
assay and the 50% inhibitory concentration (IC50) values were
determined as previously described.14,15 The concentration required
for half maximal inhibition of virus replication in a GT 1b (Con1)
replicon was determined and the data reported as EC50 values. Con-
struction of the replicon cell line has been described previously.16
Aqueous solubility was determined in phosphate buffer solution at
pH = 6.5. These data are compiled in Tables 1 and 2.
pounds 18–23 in Table 1. It should be noted that the P4 tert-butyl
group present in 14 was a fixed structural element in this series
since the SAR suggested optimal complementarity between this
lipophilic substituent and the complementary pocket of the
enzyme. In the event, esters 19 and 20 and amides 21–23 were
found to exert similar anti-NS3 protease activity in the biochemical
assay although they did not provide a significant improvement in
potency compared to 14. This observation suggested that the
immediate P4 caps were not interfacing with the enzyme surface
but were instead solvent-exposed. The PK profile of compounds
19 and 20 provided no significant improvement over the simpler
congener 14. Interestingly, compound 20, which bears a carboxylic
acid as a P4 cap, demonstrated a significant improvement in
potency in the biochemical assays across NS3 proteases represent-
ing GTs 1–3. Most notable was the IC50 value toward the GT 1a
enzyme which, at 50 pM, was 6-fold more potent than compound
14. Docking studies suggested that the enhanced potency of 20
could be attributed to hydrogen-bonding interactions between
the terminal carboxylate of 20 and both Arg-123 as well as the
backbone NH of Cys-159 (Fig. 4). While this level of activity in
the biochemical assay was significant, the PK profile of 20 was less
than optimal and hence this compound was not progressed.
As noted above, a model of 4, bound to the NS3/4a protease
enzyme complex suggested that the P4 urea moiety could poten-
tially bind to the carbonyl moiety of Ala-157 in a bidentate fashion
(Fig. 2), while P4 carbamates such as 1 interface with the enzyme
through a single H-bond interaction.12,8 Given the potency of car-
bamate 1, we sought to examine the idea that acceptable inhibition
of the NS3 protease may be achievable with substrates possessing
a single H-bond donor projected distal rather than proximal to the
P3 moiety. To this end, both N-methylated urea derivatives as well
as reverse carbamates were prepared in effort to explore this con-
cept and the results are summarized in Table 2. Synthetic schema
for the preparations of these compounds can be found in the Sup-
plemental Material.
In the course of preparing a series of P3-P4 urea analogs, it was
discovered that urea 7b, which contains
the P4 endcap (Table 1), offered an ꢀ8-fold potency advantage over
the corresponding -valine methyl ester 7a. This observed stereo-
chemical preference at P4 was recapitulated with the diastere-
omeric pair of ureas 8a/8b and 9a/9b where the -isomer showed
a several-fold increase in potency relative to the -isomer. Compu-
tational modeling suggested that the enhancement in activity
observed for compounds in the -stereochemical series was due
L-valine methyl ester as
D
L
D
L
to a beneficial hydrophobic surface interaction between enzyme
and inhibitor at the lipophilic P4 pocket of the protease, as previ-
ously reported.11b,17
In an attempt to further optimize interactions in the lipophilic
P4 pocket, we next prepared compounds 10–17 (Table 1) which
possessed the preferred stereochemistry at P4, but with R-groups
of varying size and shape. In addition to providing important struc-
tural information for maximizing potency, these compounds were
engineered with the goal of improving PK. We reasoned that the
terminal methyl ether oxygen of 10–17 might form an intramolec-
ular hydrogen-bond with the urea moiety, effectively presenting
the end of the molecule as a pseudo 5-membered ring, and thereby
masking a portion of the urea polarity and potentially improving
permeability.18,19 Compound 14 proved to be the most active in
this series, with anti-NS3 protease activity in the GT 1a and GT
3a biochemical assays ꢀ3-fold more potent than that observed
for compound 4. SAR trends in this series were sensitive to steric
bulk, with in vitro anti-NS3 protease activities generally deteriorat-
ing as R became either smaller (compounds 10–13) or larger (com-
pounds 15–17) than the tert-butyl moiety of compound 14. With
respect to PK properties, a 6-fold increase in plasma AUC was
observed for compound 14 compared to urea 4 while liver concen-
trations were found to be similar for these analogues. Interestingly,
this PK improvement was coincidental with a ꢀ50-fold increase in
aqueous solubility of 14 when compared to 4. Given these data, we
speculated that the terminal P4 ether moiety in 14 may be driving
solubility by providing a more polar terminus compared to 4. This
enhanced solubility may also explain the increase in absorption for
14 compared to 4. However, the potential for the terminal methyl
ether in 14 to facilitate the desolvation of the P4 urea through the
formation of an intramolecular hydrogen-bond that obscures the
polarity of the urea should also be considered as a source of
improved absorption of 14. Although the PK result for 14 marked
progress within the urea series, the exposure observed for this
compound was inferior to that of carbamate 1 and, hence, atten-
tion was focused on replacement of the P4 methyl ether end cap
in an effort to further modulate anti-NS3 protease activity and
improve PK.
A series of P3-P4 ureas were explored first and their anti-NS3
protease activity, antiviral properties in a HCV replicon cell-based
assay and PK profiles examined. Installation of a methyl group on
the P4 side nitrogen atom of the urea yielded 27, a molecule which
retained intrinsic potency against the GT 1a NS3 protease but
exhibited reduced potency in the GT 1b replicon cell-based assay
when compared to the parent urea analogue 25. Transposition of
the methyl group to the P3 side of the urea provided 28, a com-
pound with poor potency in the biochemical assay. While this
result appeared discouraging with respect to the hypothesis under
examination, a model of 28 bound to the NS3/4a protease complex
The P4 cap functionality explored in this part of the survey
included esters, amides and acidic groups, as exemplified by com-
Fig. 4. Compound 19 modeled into the GT 1a HCV NS3/4A protease complex
binding site.
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B.L. Venables et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
7
Fig. 5. The P4 termini of compounds 24 and 33 modeled into the HCV GT 1a NS3/4A protease complex binding site.
suggested that steric repulsion between the urea methyl sub-
stituent and the P3 tert-butyl moiety may result in a local confor-
mation in which hydrogen-bonding between the remaining urea
N–H and the carbonyl of Ala-157 was unfavorable. In order to
probe relief of this potential source of steric strain in 28, replace-
ment of the P3 tert-butyl with the corresponding sec-butyl group
was examined. This subtle but important structural modification
restored inhibitory properties against the enzyme, as exemplified
by compounds 29 and 30. Compounds 27, 29 and 30 offered com-
parable performance in the rat PK screen but each demonstrated
significantly enhanced (17 to 36-fold) liver levels when compared
to the parent urea 25. However, plasma levels for these compounds
remained relatively low and this series was not progressed.
In an effort to further the observation that the hydrogen-bond
donor could reside on either side of the P4 carbonyl oxygen atom,
we next considered a series of reverse carbamates in the context of
33–35 since the oxygen atom would present a sterically relatively
undemanding element at this site of the pharmacophore. Modeling
of carbamate 24 and reverse carbamate 33 with the NS3/4a pro-
tease complex illustrated the similarity of the hydrogen-bond dis-
tances between the carbamoyl NH of the two compounds and the
backbone carbonyl of Ala-157 (Fig. 5). The observed improvement
in potency against the NS3 protease with reverse carbamates
33–35 was notable, just 3-fold less than the parent carbamate
24. However, the PK profile of compounds 33–35 after ID dosing
was similar to the parent series and hence reverse carbamates
appeared to offer no advantage over the parent series represented
by 24. It should be noted that the use of a reverse carbamate func-
tionality at the P3-P4 position of inhibitors of serine protease has
found somewhat limited application.20 However, the activity
observed with this functionality in the current series suggests that
reverse carbamates may be a viable replacement for N-terminal
amide or carbamate capping groups.
the P3-P4 urea compounds did not yield the targeted PK parame-
ters, leading to this series being dropped from further
consideration.
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.bmcl.2018.04.009.
References
1. Mohd HK, Groeger J, Flaxman AD, Wiersma ST. Hepatology.
2013;57:1333–1342.
2. Messina JP, Humphreys I, Flaxman A, et al. Hepatology. 2015;61:77–87.
3. Simonetti RG, Cammá C, Fiorello F, et al. Ann Intern Med. 1992;116:97–102.
4. Sulkowski MS, Cooper C, Hunyady B, et al. Nat Rev. Gastroenterol Hepatol.
2011;8:212–223.
5. Ogawa E, Furusyo N, Kajiwara E, et al. The Kyushu University Liver Disease
Study [KULDS] Group. J Gastroenterol Hepatol. 2012;27:1233–1240.
6. Fried MW. Hepatology. 2002;36(Suppl. 1):S237–S244.
7. Appel N, Schaller T, Penin F, Bartenschlager R.
2006;281:9833–9836.
J
Biol Chem.
8. Scola PM, Wang AX, Good AC, et al. J Med Chem. 2014;57:1708–1729.
9. (a) Scola PM, Sun L-Q, Wang AX, et al. J Med Chem. 2014;57:1730–1752;
(b) McPhee F, Sheaffer AK, Friborg J, et al. Antimicrob Agents Chemother.
2012;56:5387–5396.
10. (a) Gao M, Nettles RE, Belema M, et al. Nature. 2010;465:96–100;
(b) Belema M, Nguyen VN, Bachand C, et al. J Med Chem. 2014;57:2013–2032;
(c) Poole RM. Drugs. 2014;74:1559–1571;
(d) Kumada H, Suzuki Y, Ikeda K, et al. Hepatology. 2014;59:2083–2091.
11. (a) Campbell JA, Good A. PCT Int Appl WO. 2002. 2002060926;
(b) Wang XA, Sun L-Q, Sit S-Y, et al. PCT Int Appl WO. 2003. 2003099274;
(c) Sin N, Good A, Venables B, Scola P, Meanwell N. PCT Int Appl WO. 2006.
2006086381.
12. Slater MJ, Amphlett EM, Andrews DM, et al. Org Lett. 2003;5:4627–4630.
13. Sheaffer AK, Lee MS, Hernandez D, et al. Antivir Ther. 2011;16:705–718.
14. Taliani M, Bianchi E, Narjes F, et al. Anal Biochem. 1996;240:60–67.
15. Drexler D, Barlow DJ, Falk P, et al. Anal Bioanal Chem. 2006;384:1145–1154.
16. Fridell RA, Qiu D, Wang C, Valera L, Gao M. Antimicrob Agents Chemother.
2010;54:3641–3650.
17. (a) Bogen SL, Pan W, Ruan S, et al. PCT Int Appl WO. 2005. 2005085275;
(b) Bogen SL, Pan W, Ruan S, et al. J Med Chem. 2009;52:3679–3688.
18. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Adv Drug Deliv Rev.
1997;23:3–25.
19. (a) Gao H, Su P, Shi Y, et al. Eur J Med Chem. 2015;90:232–240;
(b) Furet P, Caravatti G, Guagnano V, Lang M, Meyer T, Schoepfer J. Bioorg Med
Chem Lett. 2008;18:897–900;
(c) Sasaki S, Cho N, Nara Y, et al. J Med Chem. 2003;46:113–124;
(d) Ashwood VA, Field MJ, Horwell DC, et al. J Med Chem. 2001;44:2276–2285.
20. (a) Bailey MD, Bordeleau J, Garneau M, et al. Bioorg Med Chem Lett.
2013;23:4447–4452;
In summary, we have described the design of a series of P3-P4
urea-linked compounds that provided significant intrinsic antiviral
potency as well as aqueous solubility advantages over P3-P4 carba-
mate-linked tripeptide HCV NS3 protease inhibitors. The lipophilic
P4 structural component of these inhibitors was adjusted to pro-
vide for optimal potency. The concept of hydrogen-bond donor
transposition at the P3-P4 junction was successfully demonstrated
with both N-methylated ureas and reverse carbamates. Despite
several advantages discovered with the P3-P4 ureas, these deriva-
tives were characterized by permeability and exposure shortcom-
ings, presumably due to the inherent polarity of the urea motif
itself. A strategy to overcome these shortcomings was imple-
mented with moderate success but, ultimately, the PK profiles of
(b) Duan M, Kazmierski W, Crosby R, et al. Bioorg Med Chem Lett.
2012;22:2993–2996;
(c) Llinás-Brunet M, Bailey MD, Ghiro E, et al. J Med Chem. 2004;47:6584–6594;
(d) Saksena AK, Girijavallabhan VM, Lovey RG, et al. PCT Int Appl WO. 2003.
2003062265;
(e) Ohshima M, Iwase N, Sugiyama S, et al. Eur Pat Appl EP. 1995. 669317.
Please cite this article in press as: Venables B.L., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.04.009