P4 capped amides and lactams as HCV NS3 protease inhibitors with improved potency and DMPK profile

Article abstract of DOI:10.1016/j.bmcl.2009.11.094

SAR studies on the extension of P3 unit of Boceprevir (1, SCH 503034) with amides and lactams and their synthesis is described. Extensive SAR studies resulted in the identification of 36 bearing 4, 4-dimethyl lactam as the new P4 cap unit with improved po

Full text of DOI:10.1016/j.bmcl.2009.11.094

Bioorganic & Medicinal Chemistry Letters 20 (2010) 567–570
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
P4 capped amides and lactams as HCV NS3 protease inhibitors with
improved potency and DMPK profile
*
Latha G. Nair , Mousumi Sannigrahi, Stephane Bogen, Patrick Pinto, Kevin X. Chen, Andrew Prongay,
Xiao Tong, K.-C. Cheng, Viyyoor Girijavallabhan, F. George Njoroge
Chemical Research, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
SAR studies on the extension of P3 unit of Boceprevir (1, SCH 503034) with amides and lactams and their
synthesis is described. Extensive SAR studies resulted in the identification of 36 bearing 4, 4-dimethyl lac-
tam as the new P4 cap unit with improved potency (Kꢀi ¼ 15 nM, EC 90 = 70 nM) and pharmacokinetic
Received 25 September 2009
Revised 17 November 2009
Accepted 18 November 2009
Available online 22 November 2009
properties (Rat AUC (PO) = 3.52 lM h) compared to 1.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
HCV protease
Amides
Lactams
The hepatitis C virus is a major health hazard affecting over 170
million individuals worldwide1a and its infection is a leading cause
of chronic liver disease and death from liver disease in the United
states.1b–d The current standard of care treatment is a combination
serine protease and a number of novel inhibitors have been
reported.8 More recently, peptidomimetics like BILN 20619, VX-
95010 and MK-700911 are reported to show the antiviral activity
by inhibiting the replication of the virus along with our clinical
candidate SCH 503034 (Fig. 1).12 Currently, the most advanced can-
didates are telapravir (VX-950) from Vertex and Boceprevir (SCH
503034) from Schering–Plough which are in phase III clinical trials.
All the inhibitors were synthesized according to the general
Scheme 1. The gem dimethyl proline derivative 2 was prepared
by a modified published procedure.13 2 was coupled to the P3
N-Boc tert-leucine14,12 followed by acidic deprotection of the Boc
and subsequent coupling with the P4 isocyanate to afford the P4
methyl ester 4.
of subcutaneous pegylated interferon-a with oral nucleoside drug
ribavirin.2 Response rates for HCV patients having genotypes 2 or 3
on a 24 week treatment of this is 80% whereas those with genotype
1 are treated for 48 weeks with response rates of less than 50%. With
the opportunity to improve response rates, especially for genotype 1
patients, and given the side effects associated with the current ther-
apy, it is necessary to search for novel potent and drug like inhibitors
of NS3 enzyme of HCV with the intent of improving treatment out-
comes and potentially shorten treatment duration.
The NS3 protease which is located at N-terminal portion of NS3
protein has a demonstrated vital role in the replication of the HCV
virus.3 Hence there is compelling evidences4 to suggest that the
inhibition of NS3 protease would be a viable strategy for the devel-
opment of small molecules as antiviral agents. It has been deter-
mined that the HCV NS3 protease belongs to the trypsin or
chymotrypsin super family of serine protease.5 For efficient pro-
cessing, the protease forms a complex with a small polypeptide
co-factor NS4A.6 The structure data of the protease have revealed
a shallow and solvent exposed substrate binding region, where
the binding energy is mainly derived from weak lipophilic and
electrostatic interactions.7 Despite tremendous difficulty encoun-
tered in the process, intensive efforts have been focused on NS3
Hydrolysis of the methyl ester 4 with LiOH to acid 5 and by sub-
sequent coupling with the P1 unit under EDCI, HOOBt conditions
p2
p1'
cap
N
O
N
NH2
N
O
O
N
O
Ki* = 14nM
EC90 = 350nM
O
p1
p3
1
* Corresponding author.
E-mail address: latha.nair@spcorp.com (L.G. Nair).
Figure 1. Boceprevir (SCH 503034).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.11.094

568
L. G. Nair et al. / Bioorg. Med. Chem. Lett. 20 (2010) 567–570
Table 1
b,c
SAR of amides
a
OMe
OMe
OMe
N
H
N
N
O
HCl
O
O
O
O
N
N
N
O
P4
O
N
N
N
O
O
2
3
4
O
O
R
N
O
O
d
e,f
Kꢀi (nM)
O
Entry
R
EC90
—
(lM)
HNE/HCV
—
N
N
OH
N
N
O
H
O
P1
O
14
1500
O
N
N
O
N
N
O
P4
O
P4
O
6
15
16
17
18
37
0.55
—
150
75
N
5
HN
HN
HN
HN
O
Scheme 1. Synthesis of the P3 capped amide and lactam analog of 1. Reagents and
conditions: (a) tert-leucine, EDCI, HOOBt, DMF/CH2Cl2; (b) 4 M HCl/dioxane, rt; (c)
P4NCO, DIPEA, CH2Cl2; (d) LiOH, THF/MeOH/H2O; (e) P1 hydroxy allyl amide, EDCI,
HOOBt, DMF/CH2Cl2; (f) Dess–Martin periodinane.
F
F
42
N
N
N
F
O
O
O
followed by the oxidation of the resulting hydroxyl amide with
Dess–Martin Periodonane afforded the keto amide of type 6. The
P4 amide capings were synthesized using the general procedure
outlined in Scheme 2. The amine, 9 was synthesized from the cor-
responding alcohol via mesylation, displacement of the mesylate
with the azide followed by reduction of the azide 8. Condensation
of amine 9 with the anhydride 11 resulted in the imide 12. Selec-
tive reduction of the imide to the lactam was achieved via a two
step reduction sequence with lithium triethyl borohydride fol-
lowed by sodium cyano borohydride.15
All inhibitors were tested in the HCV continuous enzymatic as-
say16 using the NS4A-tethered single chain NS3 serine protease.17
The Kꢀi values reflected the equilibrium constant determined by
the reversible covalent bond formed between the ketone and ser-
ine and other interactions between the inhibitors and the en-
zyme.18 The concentration required for inhibition of 90% of virus
replication, EC90, was obtained as a measure of replicon cellular po-
tency.19 Inhibitors were tested for the activity against one of the
most structurally close related serine protease, human neutrophil
elastase (HNE) to determine the selectivity between HCV and HNE.
Based on X-ray structure of inhibitor 1 we envisioned that the
extension of P3 unit with a group having carbonyl at the appropri-
ate position would possibly engage in hydrogen bonding with Cys
159.20 Amides and their bioisosteres were one of the initial choices
and were evaluated first as the potential P4 capped inhibitors.
Amide 15 (Kꢀi ¼ 37 nM) showed 40-fold improvement in potency
compared to 14 bearing tertiary butyl carbamate P4. It is observed
91
—
280
—
23,000
—
with inhibitors 16–18 that bulky groups are not tolerated next to
the carbonyl of the amide (Table 1).
Tethering of the N-alkyl to the methyl group of amide 15 was
adopted as a method to rigidify the molecule. We discovered that
the constrained five membered lactam 19 was equipotent to the
acyclic amide 15. The six membered lactam, 20 showed twofold
improvements in potency and HNE selectivity compared to the
acyclic amide 15.
Encouraged by these preliminary results, we decided to probe
further the P4 area using substituted and bicyclic lactams (21–
23) and aromatic lactams (24, 25) and the results are shown in Ta-
ble 2. As observed with acyclic amides, substitution next to the car-
bonyl (21, Kꢀi ¼ 89 nM) resulted in sixfold loss in potency. However
gem dimethyl substitution at the 4 position was well tolerated and
seemed to have
a profound effect in cellular activity (22,
EC90 = 80 nM) with a fourfold improvement compared to 20. The
bicyclic lactam 23 (Kiꢀ ¼ 8 nM, EC90 = 60 nM) also showed
improvement in potency and selectivity. However the rat exposure
for 23 was not good enough to pursue this series further. The aro-
matic lactam 24 (Kꢀi ¼ 40 nM) was less active in the enzymatic as-
say compared to 22. Although aromatic fused six membered
lactam 25 (Kꢀi ¼ 19 nM, EC90 = 250 nM) exhibited similar enzy-
matic activity, both the replicon activity and HNE selectivity were
poor compared to 22.
The importance of carbonyl group for potency by engaging in
hydrogen bonding with Cys 159 was revealed with cyclic amine
26 which resulted in complete loss in potency. Heteroatoms were
incorporated in the lactam ring to modify the electronic property
of the carbonyl group (27 and 28). Both the carbamate 27
(Kꢀi ¼ 10 nM, EC90 = 350 nM) and urea 28 (Kꢀi ¼ 4:9 nM,
EC90 = 175 nM) were well tolerated and showed a similar or
slightly improved activity compared to the corresponding lactam
20. Unfortunately urea 28 (Kꢀi ¼ 4:9 nM, EC90 = 175 nM) exhibited
a poor DMPK profile (Table 4) and this series was discontinued.
Our earlier SAR studies and X-ray structure of inhibitors showed
that the P3 moiety binds to the S3 pocket mainly through lipophilic
interactions.7 With the discovery of six membered lactams 20 and
a,b
BocHN
BocHN
c
BocHN
OH
N3
NH2
7
8
9
O
N
d,e
BocHN
R
10
O
O
O
O
N
BocHN
BocHN
g,h
+
N
9
f
O
O
11
13
12
Scheme 2. Reagents and conditions: (a) Mesylchloride, pyridine, rt, 4 h; (b) NaN3,
DMF, 60 °C, 18 h; (c) Pd/C, H2 (1 atm), 3 h; (d) acetyl chloride, Pyr, CH2Cl2, 18 h; (e)
Cs2CO3, MeI, DMF, 4 h; (f) toluene, reflux, then Ac2O, Et3N, 90 °C; (g) LiEt3BH,
CH2Cl2, ꢁ78 °C, 15 min; (f) NaCNBH3, CH3CN, AcOH.

L. G. Nair et al. / Bioorg. Med. Chem. Lett. 20 (2010) 567–570
569
Table 2
Table 3
SAR of cyclic P4 substitution
SAR of P3 and P1 substitutions
O
O
N
N
N
N
N
N
O
O
N
N
R
O
O
O
P1
O
N
R
N
O
O
O
P3
Kꢀi (nM)
Entry
R
EC90
0.70
(
lM)
HNE/HCV
60
Kꢀi (nM)
Entry P4
P3
P1
EC90 (lM) HNE/HCV
O
19
37
N
29
30
1.8
0.110
0.080
7
N
N
20
21
14
89
0.35
—
320
90
O
O
N
N
O
9
18
O
O
N
N
31
32
1.9
7
0.045
0.080
60
N
22
17
0.08
310
O
110
23
24
8
0.06
—
613
N
O
O
O
O
O
O
N
N
N
N
33
34
35
36
19
28
5
0.080
0.070
0.060
0.070
850
1900
210
40
1500
N
O
N
25
19
0.20
250
N
26
27
2300
10
—
—
O
0.35
100
O
N
15
870
O
28
4.9
0.18
360
HN
N
HNE selectivity. Compound 34 with the cyclobutyl P1 which con-
stitutes Boceprevir 1 was less active in the enzymatic assay com-
pared to their norvaline (22) and norleucine (33) analogs but
showed a sixfold improvement in selectivity. Although the butynyl
P1 35 showed the best activity in this class, HNE selectivity and rat
exposure were poor. Cyclopropyl analog 36 (Kꢀi ¼ 15 nM,
EC90 = 70 nM) emerged as the best compound in this series with
improved potency and replicon activity as well as exposure and
HNE selectivity.
Selected analogs were profiled in the pharmacokinetic studies
and they showed moderate to good exposure in rapid rat models
(Table 4). All the lactams showed a better profile in the rapid rat
exposure compared to our clinical candidate 1. Inhibitor 34 with
22 we turned our efforts towards the optimization of the P3 and P1
residues and the results are outlined in Table 3. Since it is known
from our previous SAR studies which led to the discovery of 1 that
norvaline P1 in combination with the allyl amide P10 provided
inhibitors with very good rat PK profile12, we kept norvaline at
the P1 for our P4 and P3 optimization studies.
Our initial P3 optimization started with the unsubstituted lac-
tam 20. Tertiary butyl glycine P3 replacements with cyclohexyl,
29 (Kꢀi ¼ 1:8 nM, EC90 = 110 nM) provided improvement in both
enzyme and cellular potency but poor HNE selectivity. Indanyl
glycine at P3, 30 (Kꢀi ¼ 9 nM, EC90 = 80 nM) further improved the
cell potency but lacked selectivity. In addition both 29 and 30
had poor oral exposure in rat (Table 4) compared to 22. Analogs
of 29 and 30 with 4,4-dimethyl lactam at P4 were prepared (31,
Table 4
Rapid Rat PO AUC of selected analogs
Kꢀi (nM)
Kꢀi ¼ 1:9 nM, EC90 = 45 nM and 32, Kꢀ ¼ 7 nM, EC90 = 80 nM) but
Compound
EC90
(lM)
PO AUC lM h (10 mpk)
i
did not provide inhibitors with desired selectivity.
22
23
28
29
30
33
34
35
17
8
4.9
1.8
9
19
28
5
15
14
0.080
0.060
0.175
0.110
0.080
0.080
0.070
0.060
0.070
0.350
2.30
0.53
0.07
0.70
0.68
2.09
1.00
0.49
3.52
0.14
We clearly established with the SAR above the superiority of
4,4-dimethyl lactam at P4 and the tert-butyl glycine at P3. Our next
focus was to optimize the P1 unit keeping tertiary butyl P3 and
4,4-dimethyl lactam P4. From our previous structure activity stud-
ies12 it was demonstrated that norleucine at P1 improves the HNE
selectivity. Thus changing the P1 from norvaline (22) to norleucine
afforded 33 (Kꢀi ¼ 19 nM, EC90 = 80 nM) with similar potency both
in enzymatic and cellular assays with threefold improvement in
36
SCH503034 (1)

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Figure 2. X-ray structure 30 bound to NS3 protease.
cyclobutyl P1 exhibited sevenfold improvement in the rat exposure
and fivefold improvement in the cell potency compared to the clin-
ical candidate 1. Both compounds, 22 (Kꢀi ¼ 17 nM, EC90 = 80 nM)
and 33 (Kꢀi ¼ 19 nM, EC90 = 80 nM) with norvaline and norleucine
respectively at P1 position, showed a 15-fold improvement in
exposure compared to 1. Inhibitor 36 (Kꢀi ¼ 15 nM, EC90 = 70 nM)
stood out as the best in this class by exhibiting excellent potency
profiles with very good rat exposure (3.52 M h) and good selectiv-
ity against elastase.
The single X-ray crystal structure of a representative compound
30 is shown in Figure 2.21 The bindings of the P1, P2 and P3 residues
with their respective pockets were similar to those reported for
Bocepevir.12 The additional interaction observed is with the car-
bonyl carbon of the lactam which occupies the S4 pocket. There is
strong hydrogen bonding interaction with Cys 159 nitrogen and
the lactam carbonyl. This accounts for the enhancement in potency.
In conclusion, we identified highly potent new inhibitors as HCV
NS3 serine protease inhibitors. Systematic SAR studies of the differ-
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improvement in potency and replicon activity by 6–9-folds (23,
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i
incorporating the 4,4-dimethyl lactam as the P4 cap. Most of these
inhibitors showed improved pharmacokinetic properties compared
to 1 in rapid rat model. Our SAR studies with amides and lactams as
the P4 cap resulted in the identification of potent inhibitor 36 with
excellent potency (Kiꢀ ¼ 15 nM, EC90 = 70 nM) and selectivity
against HNE (870) and good rat exposure (3.52
lM h).
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20. For other P4 SAR reported from our reserach see: (a) Venkatraman, S.;
Blackman, M.; Wu, W.; Nair, L.; Arasappan, A.; Padilla, A.; Bogen, S.; Bennett, F.;
Chen, K.; Pichardo, J.; Tong, X.; Prongay, A.; Cheng, K.-C.; Girijavallabhan, V.;
George, N. F. Bioorg. Med. Chem. 2009, 17, 4486; (b) Bogen, S. L.; Pan, W.; Ruan,
S.; Nair, L. G.; Arasappan, A.; Bennett, F.; Chen, K. X.; Jao, E.; Venkatraman, S.;
Vibulbhan, B.; Liu, R.; Cheng, K.-C.; Guo, Z.; Tong, X.; Saksena, A. K.;
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X.; Nair, L.; Vibulbhan, B.; Yang, W.; Arasappan, A.; Bogen, S. L.; Venkatraman,
S.; Bennett, F.; Pan, W.; Blackman, M. L.; Padilla, A. I.; Prongay, A.; Cheng, K.-C.;
Tong, X.; Shih, N.-Y.; Njoroge, F. G. J. Med. Chem. 2009, 52, 1370.
21. X-ray crystal coordinates are deposited in the Protein Data Bank and the PDB
number is 3KN2.
Acknowledgements
The authors wish to thank virology, DMPK and Structural
Chemistry group of Schering-Plough Research Institute for their
help in in vitro, in vivo and X-ray crystal studies respectively and
Dr. Ronald Doll for his insightful comments.
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