Potent ketoamide inhibitors of HCV NS3 protease derived from quaternized P1 groups

Article abstract of DOI:10.1016/j.bmcl.2010.02.051

Blood borne hepatitis C infections are the primary cause for liver cirrhosis and hepatocellular carcinoma. HCV NS3 protease, a pivotal enzyme in the replication cycle of HCV virus has been the primary target for development of new drug candidates. Boceprevir and telaprevir are two novel ketoamide derived inhibitors that are currently undergoing phase-III clinical trials. These inhibitors include ketoamide functionality as serine trap and have an acidic alpha-ketoamide center that undergoes epimerization under physiological conditions. Our initial attempts to arrest this epimerization by introducing quaternary amino acids at P₁ had resulted in significantly diminished activity. In this manuscript we describe alpha quaternized P₁ group that result in potent inhibitors in the enzyme assay and demonstrate cellular activity comparable to boceprevir.

Full text of DOI:10.1016/j.bmcl.2010.02.051

Bioorganic & Medicinal Chemistry Letters 20 (2010) 2151–2155
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Potent ketoamide inhibitors of HCV NS3 protease derived from quaternized
P1 groups
*
Srikanth Venkatraman , Francisco Velazquez, Wanli Wu, Melissa Blackman, Vincent Madison,
F. George Njoroge
Schering Plough Research Institute, K15-MS 3545, 2015, Galloping Hill Road, Kenilworth, NJ 07033, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Blood borne hepatitis C infections are the primary cause for liver cirrhosis and hepatocellular carcinoma.
HCV NS3 protease, a pivotal enzyme in the replication cycle of HCV virus has been the primary target for
development of new drug candidates. Boceprevir and telaprevir are two novel ketoamide derived inhib-
itors that are currently undergoing phase-III clinical trials. These inhibitors include ketoamide function-
ality as serine trap and have an acidic alpha-ketoamide center that undergoes epimerization under
physiological conditions. Our initial attempts to arrest this epimerization by introducing quaternary
amino acids at P1 had resulted in significantly diminished activity. In this manuscript we describe alpha
quaternized P1 group that result in potent inhibitors in the enzyme assay and demonstrate cellular activ-
ity comparable to boceprevir.
Received 2 November 2009
Revised 10 February 2010
Accepted 10 February 2010
Available online 14 February 2010
Keywords:
HCV
NS3 protease
Boceprevir
Ó 2010 Elsevier Ltd. All rights reserved.
Hepatitis C virus is the primary etiological agent responsible for
non A, non B infections of the liver.1,2 The prognosis for patients in-
fected with hepatitis C is poor with majority of these infections
turning chronic. In many cases these infections progress to liver
cirrhosis and liver carcinoma.3,4 Peginterferon in combination with
antiviral ribavirin is the primary standard of care, which is effective
in ꢀ40% of genotype-1 infected patients.5–9 Patients infected with
genotype-2 or 3 respond better to peginterferon with >80% of
(Fig. 1) (1)16 and telaprevir17 are two novel ketoamide derived inhib-
itors that has been progressed to phase-III clinical trials.
Boceprevir and telaprevir are ketoamide containing inhibitors
that have a P1 stereocenter that readily epimerizes in human ser-
um under physiological conditions. The (S)-diastereomer at P1 site
is the active antipode whereas the (R)-isomer is less potent.
Several unsuccessful attempts have been made to avoid this
epimerization by introducing a quaternary amino acid at P1 result-
ing in significant loss in potency.18,16 The significant loss in activity
could potentially be attributed to the presence of quaternary cen-
ter at the alpha position of the ketoamide carbonyl group, that
could hinder serine-139 from attacking the carbonyl moiety. In
this manuscript, we disclose a series of ketoamide derived inhibi-
tors containing small cyclic quaternary amino acid derived P1
residues that demonstrate similar potency to our first generation
compound 1.
patients demonstrating
treatment.
a sustained virologic response after
Lack of effective methods to treat genotype-1 HCV infections
and patients relapsing from failed peginterferon/ribavirin therapy
necessitates development of new drugs. Significant efforts are
now directed towards development of therapies that target key
viral enzymes vital to HCV replication and maturation.
Hepatitis C virus is a positive strand virus which encodes for a sin-
gle polyprotein of ꢀ3000 amino acids. This polyprotein that contain
all the structural and functional proteins is post-translationally
modified by a single HCV NS3 serine protease. This protease with
the assistance of the cofactor NS4A catalyzes the cleavage of the
NS3-NS4A, NS4A-NS4B, NS4B-NS5A, and NS5A-NS5B junction to
form functional proteins.10–12 HCVNS3 protease has a shallow active
site on the surface of the enzyme that catalyzes cleavage of a cys-
teine–serine or a cysteine–threonine bond.13–15 Inhibition of this
key enzyme has been extensively investigated in an effort to develop
potential drugs for the treatment of HCV infections. Boceprevir
An investigation of X-ray structure of 1 bound to the NS3 prote-
ase revealed that the catalytic serine-139 attacked the ketoamide
group of the inhibitor from the Re face. This resulted in orientation
of amide group towards His-57 into the oxy-anion hole. This is in
O
H
NH2 Boceprevir
Ki* = 14 nM
N
N
H
N
O
O
HN
EC90 = 0.35 µM
O
O
1
* Corresponding author. Tel.: +1 908 740 3758; fax: +1 908 740 7152.
E-mail address: Srikanth.Venkatraman@spcorp.com (S. Venkatraman).
Figure 1.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.02.051

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S. Venkatraman et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2151–2155
in cyclic sulfinate that was oxidized with ruthenium trichloride
O
O
H
N
resulting in cyclic sulfate 5.20 Reaction of 5 with NaH and ethyl
2-(diphenylmethyleneamino)acetate yielded cyclopropyl derived
amino acid21 6 which was hydrolyzed to form amine salt 7 using
aq 1 M HCl. The amine salt 7 was treated with di-tert-butyl dicar-
bonate to form Boc-protected compound 8. Analysis of 8 by NMR
demonstrated that the ethyl group was cis to the amino group. This
was confirmed by a positive NOE enhancement between the carba-
mate NH proton and the ethyl group attached to the cyclopropyl
ring. Reduction of ester 8 with LiBH4 followed by oxidation of the
resultant alcohol with Dess–Martin reagent resulted in aldehyde
9. Aldehyde 9 was treated with acetone cyanohydrin resulting in
10, which was converted to hydroxy ester 11 by refluxing with
methanolic HCl followed by Boc protection, Hydrolysis of methyl
ester of compounds 11 followed by coupling with appropriate
amines using HATU yielded amides of type 12, which were depro-
tected with 4 M HCl in dioxane to form amine salts of type 13.
Alternatively aldehyde 9 was subjected to Passerini reaction22,23
with alkylisonitriles and acetic acid to directly install secondary
hydroxyamide groups resulting in intermediate of type 12 that
was converted to amine salt 13. Other cyclopropyl P1 analogs were
also synthesized using similar methods.
H2N
R1
H2N
R1
R
OH
O
2
3
Cis to acid
Cis to amine
Figure 2.
contrast to acid derived inhibitors such as BILN-2061 which binds
from the Si face of the carbonyl group with one of the oxygens of
the carboxylic acid being directed into the oxy-anion hole while
other forming a hydrogen bond with His-57.19 It is also well known
that BILN-2061 has a vinyl cyclopropyl derived amino acid at P1.
We reasoned that the difference in binding modes of the ketoa-
mide and acid derived inhibitors required different spatial arrange-
ment of the alkyl groups attached to the cyclopropyl moiety (R1,
Fig. 2) in the ketoamide and acid series of inhibitors to occupy
the S1 pocket effectively.
For an optimum occupation of the S1 pocket in the acid series of
inhibitors the R1 group should be cis to the carboxylic acid,
whereas in the ketoamide series of inhibitors the R1 residue should
be oriented away from the acid such that it is cis to the amino
group. With this paradigm we decided to explore quaternary ami-
no acids at P1 in the ketoamide series derived from cyclopropyl and
cyclobutyl groups.
Synthesis of cyclobutyl derived P1 fragment was initiated from
epichlorohydrin 14 as outlined in Scheme 2. Treatment of 14 with
Br
Cl
a
b
Cl
The synthesis of P1 cyclopropyl derived hydroxy amide frag-
ment is shown in Scheme 1. Reaction of diol 4 with SOCl2 resulted
O
OBn
14
15
O
S
b
OH
a
O
O
O
O
O
O
HO
CH3
O
O
CH3
c
OC2H5
C2H5O
OC2H5
C2H5O
4
5
O
O
C6H5
C6H5
BnO
16
ClH3N
N
c
17
OC2H5
OC2H5
Boc
O
O
O
7
6
H
CH3
CH3
N
OC2H5
C2H5O
e
g
O
OC2H5
d
Boc
N
d
e
OC2H5
H
C2H5
C2H5
19
NOE
8
18
CH3
O
OH
CN
O
OH
H
BocHN
BocHN
f
N
BocHN
f
H
H
CN
Boc
9
10
CH3
CH3
C2H5
20
C2H5
21
OH
OCH3
g
BocHN
h
OH
O
OH
OCH3
NHR2
BocHN
ClH3N
i
11
h
CH3
h
O
O
OH
OH
NHR2
NHR2
BocHN
ClH3N
C2H5
22
C2H5
23
O
O
12
CH3
13
CH3
Scheme 2. Reagents and conditions: (a) BnBr, HgCl, 12 h, 150 °C, 70%; (b)
H2C(COOC2H5)2, NaH, 110 °C, 72 h, 35%; (c) (i) Pd(OH)2, H2, EtOAc, 2 h, 70%; (ii)
Dess Martin reagent, CH2Cl2, 70%; (d) (i) C2H5PPH3Br, tBuOK, THF; (ii) H2/Pd/C,
MeOH; (e) (i) LiOH, THF/MeOH; (ii) DPPA, tBuOH, reflux; (f) (i) LiBH4, THF; (ii) Dess–
Martin reagent; (g) acetone cyanohydrin, Et3N; (h) (a) 6 M methanolic HCl; (b)
Boc2O, CH2Cl2 (i) (i) aq LiOH, THF/H2O; (ii) R2NH2, HATU, NMM; (iii) 4 M HCl in
dioxane.
Scheme 1. Reagents and conditions: (a) (i) SOCl2, CCl4, 80 °C; (ii) RuCl3ꢁ3H2O, HIO5,
CCl4/CH3CN; (b) NaH, DME, (C6H5)2C@NCH2COOC2H5 reflux, 2 h; (c) (i) aq HCl, THF;
(d) Boc2O, Pr2NEt, CH2Cl2; (e) (i) LiBH4, THF; (ii) Dess–Martin reagent; (f) acetone
i
cyanohydrin, Et3N; (g) (a) 6 M methanolic HCl reflux; (b) Boc2O, CH2Cl2 (h) (i) aq
LiOH, THF/MeOH; (ii) R2NH2, HATU, NMM; (i) 4 M HCl in dioxane, rt.

S. Venkatraman et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2151–2155
2153
Table 1
O
BocHN
OH
O
H
N
NH
COOCH3
N
N
H
N
H
N
a
O
COOCH3
.HCl
O
N
H
24
BocHN
R1
S
O O
O
O
O
25
Kiꢂ
(lM)
Entry
R1
29
30
31
32
H
CH3
CH3CH2
CH3CH2CH2
18.0
3.0
0.11
0.70
c
b
COOCH3
N
H
H
N
N
R4
O
O
26
the EC90.
28 The effect of substitution on the cyclopropyl group with
various alkyl groups is shown in Table 1.
OH
Incorporation of unsubstituted cyclopropyl ketoamide at P1 re-
d or e
H
+
-
N
NHR2
sulted in compound 29 with a Kꢂi = 18
lM. The corresponding nor-
valine P1 analog demonstrated a Kꢂ = 5 nM indicating a huge loss in
N
N
H
H
i
O
O
O
N
N
potency by quaternizing P1. The effect of substitution at P1 cyclo-
propyl ring was evaluated by incorporating alkyl group syn to
amine. Introduction of a methyl group on the cyclopropyl ring re-
R4
O
CH3
O
O
27
sulted in compound 30 with a Kꢂi = 3.0
lM, a six fold improvement
in activity compared to the unsubstituted cylopropyl derivative 29.
O
Replacement of the methyl group with ethyl substituent resulted
H
+
in compound 31 which had a binding of Kꢂi = 0.11
lM. Thus, the
NHR2
N
-
ethyl group had a profound effect on binding with a 160-fold
improvement in binding compared to the cyclopropyl compound
29. However, extension of 29 with propyl group resulted in com-
H
N
H
N
O
R4
O
CH3
pound 32 (Kꢂi = 0.7
ethyl compound 31.
lM) a sevenfold loss in activity compared to
28
Scheme 3. Reagents and conditions: (a) HATU, NMM, CH2Cl2/DMF; (b) (i) 4 M HCl
in dioxane; (ii) R4NCO, NMM; (c) (i) aq LiOH, THF/MeOH; (ii) 13, HATU, NMM; (d)
when (R2 = cyclopropyl) Dess–Martin reagent CH2Cl2; (e) when (R2 = H), EDCI,
Cl2CHCOOH, toluene.
We also evaluated the effect of cyclobutyl group at P1 (Table 2).
P1 diastereomers in the cyclobutyl series were not readily separa-
ble in HPLC; therefore they were assayed as mixtures. Introduction
of unsubstituted cyclobutyl at P1 resulted in compound 33 with a
binding (Kꢂi = 15
l
M) similar in activity to the cyclopropyl deriva-
tive 29. Addition of a methyl group on the cyclobutyl ring resulted
in compound 35 with a Kꢂi = 0.42
M whereas addition of an ethyl
group resulted in compound 36 with a Kꢂi = 0.19
M. The introduc-
benzyl bromide in the presence of HgCl yielded benzylated alcohol
15 in 70% yield.24 Treatment of 15 with diethylmalonate and NaH
formed cyclobutyl derivative 16. The benzyl ether of 16 was cata-
lytically hydrogenated with H2/Pd(OH)2 and the resulting alcohol
was further oxidized to ketone 17 using Dess–Martin reagent.
Ketone 17 was elaborated using Wittig reaction by treatment of
ethyl phosphonium bromide and KtBuO. The resulting olefin was
catalytically hydrogenated to generate ethyl substituted cyclobutyl
derivative 18. Basic hydrolysis of ethyl ester with one equivalent of
lithium hydroxide resulted in the selective hydrolysis of the ethyl
ester syn to the alkyl group. The obtained acid was treated with
DPPA and tert-butanol to induce a Curtius rearrangement to form
Boc-protected amino ester 19, which was converted to the P1 hy-
droxy amides of type 23 using similar steps outlined for the syn-
thesis of the cyclopropyl derivative in Scheme 1.
l
l
tion of an ethyl substituent resulted in a dramatic improvement in
binding, similar to the effect of this substitution observed in the
cyclopropyl series. However, incorporation of a polar substituent
such as a hydroxyl group was not well tolerated resulting in com-
pound 34 (Kꢂi = 89
lM).
Having identified that a cylopropyl or a cyclobutyl group with
an ethyl substitution provided potent inhibitors, we next explored
the effect of variation of the P3 and P3 capping groups to optimize
the binding activity and cellular potencies. Since P1 diasteromer in
the cyclopropyl series were readily separable it was used for fur-
Table 2
The methodology used for the synthesis of desired inhibitors is
outlined in Scheme 3. Coupling of dimethyl cyclopropylproline
derivative 2425,26 with tert-butylglycine using HATU resulted in
compound 25.16 Deprotection of the Boc group 25 followed by
treatment of the resultant amine salt with appropriate isocyanate
yielded compounds of type 26, which was further coupled with
P1 segment of type 13 to yield hydroxy amides of type 27 that were
oxidized to form the corresponding ketoamide inhibitors of type
28. P1 diastereomers of synthesized inhibitors were separated
using YMC diol column under normal phase HPLC conditions.
Synthesized inhibitors were evaluated for inhibition of NS3
protease in a continuous enzyme binding assay to obtain binding
constant Kꢂi .27 Compounds that demonstrated good binding were
further evaluated in a replicon based cellular assay to establish
O
H
+
-
N
NH
N
H
N
H
N
O
O
S
O O
O
R1
O
Kiꢂ
(lM)
Entry
R1
33
34
35
36
H
OH
CH3
15
89
0.42
0.19
CH3CH2

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S. Venkatraman et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2151–2155
Table 3
Table 4
O
O
H
N
H
N
NH2
NH
N
N
H
N
H
H
N
H
N
N
O
O
O
O
R4
R4
O
O
O
R3
CH3
CH3
O
R3
Kiꢂ
(lM)
Entry
R4
R3
EC90
1.6
(lM)
Kiꢂ
(lM)
Entry
R4
R3
EC90
0.5
(lM)
O
O
N
O
N
37
0.082
42
0.058
O
O
O
O
S
N
S
S
38
39
0.20
0.95
2.7
–
N
O
43
45
0.023
0.015
0.40
0.40
O
O
O
S
O
O
40
41
0.50
0.6
–
–
O
ing we also reasoned that this amino acid required an alkyl substi-
tuent projecting from the ring such that it was oriented syn to the
amino group to effectively occupy S1 pocket. Efficient syntheses of
these P1 amino acids were developed and incorporating them into
the inhibitors demonstrated early that an ethyl substituent was
preferred yielding compounds 31 and 36 with modest binding
activity. In an effort to further improve binding and cellular activ-
ity, a systematic variation of P3 and P3 capping groups were inves-
tigated. Introduction of dimethylglutarimide derived P3 capping
resulted in compound 37 with improved binding activity
S
O
O
ther SAR studies. The effects of these modifications are summa-
rized in Table 3.
Replacement of tert-butyl sulfone derived P3 capping of 31 with
(Kꢂi = 0.082
lM) and EC90 = 0.5 lM. Further SAR investigation at
dimethylglutarimide derived cap29 resulted in compound 37 with
P01 identified the beneficial effect of introducing the primary amide
functionality. Incorporation of P01 primary ketoamide resulted in
a Kꢂi = 0.082
l
M and EC90 = 0.5
mide30 derived P3 cap resulted in compound 38 with a Ki = 0.2
and EC90 = 2.7 M. We next evaluated the effect of modification of
l
M. Introduction of methꢂylsulfona-
l
M
inhibitors 43 and 45 that demonstrated Kꢂi = 0.023
lM
and
l
0.015
lM. This was similar in potency to our first generation clin-
P3 substitution. Incorporation of b-methylcyclohexylglycine at P3
ical candidate 1. These compounds also demonstrated good cellu-
lar activity in the replicon based cellular assay achieving an
EC90 = 0.40 lM which is similar to that of 1. Thus, we have demon-
position resulted in compound 39 with diminished activity
(Kꢂi = 0.95
l
M) compared to tert-butyl derivative 31. Similarly
incorporation of indanylglycine at P3 resulted in compound 40
with binding Kꢂi = 0.5
M and introduction of cyclohexylglycine
yielded compound 41 with Kꢂi = 0.6
M. Both these modifications
strated that incorporation of a P1 quaternary amino acid is well tol-
erated in the ketoamide series of inhibitors achieving similar
binding and cellular potency to boceprevir. However, it is unclear
that if these compounds inhibit HCV protease by reversibly trap-
ping serine-139. Further studies are in progress to establish if the
gain in potency was mainly due to hydrogen bonds and lipophilic
interactions only or do these compounds still interact with the en-
zyme covalently.
l
l
yielded compounds with lower activity than the tert-butyl glycine
P3 substitution.
We next evaluated the replacement of P01 cyclopropyl amide
with a primary amide (Table 4). Replacement of cyclopropylamide
of compound 37 with primary amide resulted in compound 42
with improved binding (Kꢂi = 0.058
l
M); however it was less po-
tent in the cellular assay (EC90 = 1.6
lM) than 37. The replacement
References and notes
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l
M
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