Design and optimization of novel (2S,4S,5S)-5-amino-6-(2,2-dimethyl-5-oxo- 4-phenylpiperazin-1-yl)-4-hydroxy-2-isopropylhexanamides as renin inhibitors

Article abstract of DOI:10.1016/j.bmcl.2012.05.092

Introduction of the 2,2-dimethyl-4-phenylpiperazin-5-one scaffold into the P₃-P₁ portion of the (2S,4S,5S)-5-amino-6-dialkylamino-4- hydroxy-2-isopropylhexanamide backbone dramatically increased the renin inhibitory activity without

Full text of DOI:10.1016/j.bmcl.2012.05.092

Bioorganic & Medicinal Chemistry Letters 22 (2012) 4561–4566
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and optimization of novel (2S,4S,5S)-5-amino-6-(2,2-dimethyl-5-oxo-4-
phenylpiperazin-1-yl)-4-hydroxy-2-isopropylhexanamides as renin inhibitors
Yuji Nakamura a,f, Chie Sugita a, Masaki Meguro a, Shojiro Miyazaki a, Kazuhiko Tamaki a,
Mizuki Takahashi b, Yoko Nagai c, Takahiro Nagayama d, Mikio Kato e, Hiroshi Suemune f,
Takahide Nishi a,
⇑
a Lead Discovery & Optimization Research Laboratories I, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
b Lead Discovery & Optimization Research Laboratories II, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
c Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
d Cardiovascular-Metabolics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
e Frontier Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
f Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Introduction of the 2,2-dimethyl-4-phenylpiperazin-5-one scaffold into the P3–P1 portion of the
Received 15 May 2012
Revised 23 May 2012
Accepted 29 May 2012
Available online 4 June 2012
(2S,4S,5S)-5-amino-6-dialkylamino-4-hydroxy-2-isopropylhexanamide backbone dramatically increased
the renin inhibitory activity without using the interaction to the S3 pocket. Compound 31 exhibited
>10,000-fold selectivity over other human proteases, and 18.5% oral bioavailability in monkey.
sp
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Renin inhibitor
Hypertension
Ketopiperazine
Structure-based drug design
X-ray crystallography
Hypertension is the most prevalent cause for cardiovascular
diseases, such as heart failure, stroke and kidney failure.1 It has
been estimated that there are currently about 1 billion people
who suffer from hypertension. Although lowering blood-pressure
can considerably reduce the above risks, about 70% of patients with
hypertension still do not reach their target blood pressure levels.2
Thus, well-tolerated effective medicines for sufficient blood pres-
sure control are desired.
The renin–angiotensin–aldosterone system (RAAS) controls
blood pressure and body fluid electrolytes homeostasis.3 In this
system, renin is the first rate-limiting step which leads to genera-
tion of angiotensin I. Inhibition of this step would not only provide
a better potential for the blood pressure lowering effect and end
organ protection,4 but also cause fewer mechanism-based adverse
events than the current therapeutic medicines, angiotensin con-
verting enzyme inhibitors and angiotensin receptor 1 blockers, that
target downstream events of the RAAS pathway.5
skiren),7 piperazine 3 (ACT-077825, MK-8141),8 and alkyl amine 4
(VTP-27999)9 with different renin active-site binding topologies
have entered human clinical trials (Fig. 1). To date, aliskiren is
the only compound which has been launched to the market.2b
Recently, we and Novartis group discovered novel renin inhibi-
tors (2S,4S,5S)-5-amino-6-dialkylamino-4-hydroxy-2-isopropyl-
hexanamides, replaced a chiral center at the 7-position of 8-
phenyloctanamides with nitrogen, as exemplified by compound 5,
respectively (Fig. 2).10,11 This replacement offers several advantages
over 8-phenyloctanamides such as decrease in chemical complex-
ity, ease of synthesis, and accessibility to the structure–activity
relationship (SAR) studies. However, compound 5 was less active
than aliskiren and the potential attractiveness of this series for
more extensive investigations was limited.11 Thus, we attempted
to modify the P3–P3sp–P1 portion of compound 5 to find a new lead
compound. In this letter, we report the design and initial optimiza-
tion of novel (2S,4S,5S)-5-amino-6-(2,2-dimethyl-5-oxo-4-phen-
ylpiperazin-1-yl)-4-hydroxy-2-isopropyl-hexanamides.
Accordingly, several renin inhibitors based on diverse scaffolds
such as peptidomimetic 1 (remikiren),6 8-phenyloctanamide 2 (ali-
By comparison of the P3 and P1 pharmacophores of peptidomi-
metic 1 and compound 5, we initially designed the tethered com-
pound (General structure A), bearing a phenyl group appended to a
piperidine ring directly (Fig. 2).12 This piperidine ring was intended
⇑
Corresponding author. Tel.: +81 3 3492 3131; fax: +81 3 5436 8563.
E-mail address: nishi.takahide.xw@daiichisankyo.co.jp (T. Nishi).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.05.092

4562
Y. Nakamura et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4561–4566
HN
N
MeO
OH
H
N
O
OH
H2N
NH2
H
N
S
O
N
H
O
O
O
O
O
OH
MeO
1 (Remikiren)
2 (Aliskiren)
H
N
H
N
H
N
H
O
HN
H
N
H
O
N
MeO
N
H
O
H
H
O
Cl
O
Cl
O
O
Cl
3 (ACT-077825, MK-8141)
4 (VTP-27999)
Figure 1. Structures of renin inhibitors.6–9
P2
HN
N
P1'
O
OH
H
N
S
O
N
H
O
O
OH
P1'
P1'
P2'
P2'
sp
sp
P3
P3
OH
H
OH
H
N
MeO
MeO
H2N
N
N
NH2
H2
N
N
NH2
P3
P1
O
O
O
N
O
O
1
O
O
P1
sp
P1
P3
P1'
P2'
MeO
OH
P3
P3
H
N
H2
N
NH2
General structure A
General structure B
O
O
O
N
MeO
P3
P1
5
Figure 2. Design of a new series of (2S,4S,5S)-5-amino-6-(4-phenylpiperazin-1-yl)-4-hydroxy-2-isopropylhexanamides.
to avoid any chiral center at the P1 position and utilize our syn-
thetic procedure developed for the synthesis of compound 5.13 At
the same time, a methoxypropoxy sidechain was installed to the
ortho or meta position of the phenyl portion in the hope to further
duction of geminal dimethyl groups at the 60 position of the
ketopiperazine ring could enhance potency through additional
hydrophobic interactions with the S1 pocket (Fig. 3b). To test this
hypothesis, we prepared compound 9. As expected, rac-9 exhibited
dramatically improved potency in both the purified human and the
cynomolgus monkey plasma renin assays. On the other hand,
introduction of geminal dimethyl groups into the 20 position,
which might be tolerated through rotation around C6-N10, showed
no improvement (compound 10). A further enhancement was ob-
served when rac-9 was converted to optically active (2S,4S,5S)-9.
increase potency by interaction with the S3 pocket.12c,14 As the
sp
next step, we considered the piperazine ring was proposed to have
a similar conformation compared to the piperidine ring. To reduce
the number of basic nitrogen and electron density on the tethered
benzene ring, the ketopiperazine analogue (General structure B)
was eventually designed as an alternative for the piperazine ring.
An early SAR study of the P3–P3sp–P1 portion found that the
ketopiperazine ring was resulting in higher potencies as compared
to the piperidine ring as a P1 motif (Table 1, rac-6 vs rac-7), and the
sp
As the next step, we modified the P3 aryl sidechain, which is
essential for aliskiren to contribute to high potency (Table 2).12c,14
To our surprise, compounds 11–13 with a shortened chain length
exhibited strong inhibitory activities against human renin with
only slight reductions in monkey plasma. In addition, compound
sp
ortho position was preferable for the P3 aryl sidechain than the
meta position (rac-7 vs rac-8).15 These results were explained by
the X-ray crystal structure of compound 7 in complex with human
renin; a hydrogen bond interaction was observed between Thr77
and the carboxamide oxygen of the ketopiperazine with a distance
of 2.7 Å, and the methoxypropoxy sidechain was well accommo-
sp
14 lacking the P3 aryl sidechain retained strong human renin
inhibitory activity. These interesting results prompted further mod-
ifications of the P3 portion with small substituents (Table 3).
Introduction of small substituents to the ortho position retained
high human renin inhibitory activities (compounds 15–17, and 23).
On the other hand, introduction to the meta position (compounds
18, 19, and 24) resulted in decreased potencies except for com-
pound 20. However, incorporation of an additional substituent to
dated by the S3 (Fig. 3a).16 Thus, compound 7, which possessed
sp
modest potency, was selected as a reasonable starting point for
further chemical modification. The superposition of the X-ray crys-
tal structures of compound 7 and aliskiren (2) suggested that intro-

Y. Nakamura et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4561–4566
4563
Table 1
In vitro activities of renin inhibitors with P3–P3sp–P1 modificationsa
OH
H
N
H2
N
R
NH2
O
O
Compound
R
Purified human renin IC50 (nM)
370
Monkey plasma renin IC50 (nM)
MeO
O
O
N
N
rac-6
12,500
2800
2'
O
MeO
N
rac-7
130
6'
O
N
MeO
MeO
O
O
N
N
rac-8
rac-9
9
400
3.3
1.2
3000
10
O
O
N
N
MeO
MeO
O
O
N
N
5.3
O
rac-10
170
875
N
a
Compounds were obtained as fumarate salts.
Figure 3. (a) The X-ray structure of ketopiperazine analogue 7 in complex with human renin;16 (b) Superposition of the crystal structures of aliskiren (2) (PDB 2V02;7 violet)
and 7 (green) in the S1 pocket.
Table 2
the ortho position of meta-substituted analogues recovered high
human renin inhibitory activities (compounds 21, 22 and 25–27).
The chloro group was suggested to be the most effective substitu-
sp
In vitro activities of renin inhibitors with P3 aryl sidechain modificationsa
OH
H
H2
N
N
N
NH2
ent of these for the ortho position, and the chloro analogues 17 and
25 exhibited excellent potencies in both purified human and mon-
key plasma renin assays. This SAR study suggested that the pres-
ence of a lipophilic substituent at the ortho position is important
within the ketopiperazine series to obtain high potency without
O
O
O
R
N
Compound
R
Purified human
renin IC50 (nM)
Monkey plasma
renin IC50 (nM)
sp
a P3 sidechain. The crystal structure of compound 17 in complex
sp
with human renin evidenced that 17 did not indeed utilize the S3
.
9
O(CH2)3OMe
O(CH2)2OMe
OCH2OMe
OMe
1.2
1.7
1.4
1.9
3.1
5.3
9.8
6.4
19
Surprisingly, the chloro substituent was pointing into the opposite
11
12
13
14
direction of the S3sp, which would provide additional potency
through a halogen–p interaction with the Phe112 (Fig. 4). We as-
sume that the structural feature of 4-phenylketopiperazine, which
maintains orthogonality between benzene and ketopiperazine
H
49
a
Compounds were obtained as fumarate salts.

4564
Y. Nakamura et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4561–4566
Table 3
Table 5
In vitro activities of renin inhibitors with modifications of P3 phenyl portionsa
Monkey PK profile of compound 31
OH
H
OH
H
N
H2N
N
N
NH2
H2
N
O
O
O
O
O
N
2
5
3
N
F
N
R
6
Cl
Cynomolgus monkey
(10 mg/kg p.o.)
(1 mg/kg i.v.)
F (%)
18.5
576
2109
14.7
16.3
10.8
Compound
R
Purified human
renin IC50 (nM)
Monkey plasma
renin IC50 (nM)
Cmax (ng/mL)
AUC0–24 (ng h/mL)
CL (mL/min/kg)
Vss (L/kg)
13
15
16
17
18
19
20
21
22
23
24
25
26
27
2-OMe
2-F
2-Me
2-Cl
3-OMe
3-F
3-Cl
2,3-F,F
2,5-F,F
2,6-F,F
3,5-F,F
2-Cl-5-F
2,5-Cl,Cl
1.9
2.2
1.7
1.4
4.2
3.0
2.1
2.0
2.0
2.4
5.5
2.1
2.1
2.4
19
30
24
7.0
58
23
25
11
30
12
90
7.0
28
33
T1/2 (h)
rings, might be one factor contributing to show high potency with-
out using S3 interaction, which is essential for aliskiren.12c,14
sp
Having established optimal substitution patterns for the P3 phe-
nyl portion, we turned our attention to optimize the P2 portion
0
(Table 4). Within the 2-chlorophenyl series, increased human renin
inhibitory activities were observed when alkyl groups were in-
2-Cl-5-OMe
0
a
stalled to the P2 portion (compounds 28–30). The 2-chloro-5-fluo-
Compounds were obtained as fumarate salts.
rophenyl series showed slightly reduced potencies compared to
the corresponding 2-chlorophenyl series (compounds 31–33). In
each series, the corresponding (2S)-2-methylbutyl analogues (29
and 32) exhibited excellent potencies. However, these analogues
were found to show poor metabolic stability in cynomolgus mon-
key liver microsomes (Table 4).17 Based on these results, com-
pound 31 was selected to evaluate the pharmacokinetics profile
as the metabolically most stable representative of this series. The
pharmacokinetics study (cynomolgus monkey, 10 mg/kg, p.o.)
indicated that compound 31 had 18.5% bioavailability and 10.8 h
half-life (Table 5). In addition, compound 31 showed >10,000-fold
selectivity over other proteases such as BACE-1, chymotrypsin,
cathepsin D, and trypsin. To the best of our knowledge, 31 is the
first low nanomolar renin inhibitor, which showed great enzyme
selectivity without using the interaction of S3sp in aliskiren related
series.
Our divergent synthetic route for the preparation of (2S,4S,5S)-
5-amino-6-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)-4-hydr-
oxy-2-isopropylhexanamides is depicted in Scheme 1. The key
intermediate
N-(2-nitrobenzenesulfonyl)
(Ns)18
protected
aziridine 34 was prepared according to the procedure reported re-
Figure 4. S1–S3 region of the crystal structure of compound 17 in complex with
human renin.16
cently.13 Ring opening of 34 with the corresponding ketopipera-
Table 4
In vitro activities and metabolic stabilities of renin inhibitors with modifications of P3 and P2 portionsa
0
OH
H
H2
N
N
N
R2
O
O
2
5
N
R1
Compound
R1
R2
Purified human
renin IC50 (nM)
Monkey plasma
renin IC50 (nM)
Metabolic stabilityb,c
(MLM, % remaining)
28
29
30
31
32
33
2-Cl
2-Cl
2-Cl
2-Cl-5-F
2-Cl-5-F
2-Cl-5-F
n-butyl
(2S)-2-methylbutyl
cyclohexyl
n-butyl
(2S)-2-methylbutyl
cyclohexyl
1.0
1.0
1.0
2.0
1.4
1.9
9.0
2.0
11
25
8.0
5.0
39.2
8.4
17.5
52.2
1.9
38.0
a
b
c
Compounds were obtained as fumarate salts.
MLM = monkey liver microsomes.
Percent remaining after 30 min.

Y. Nakamura et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4561–4566
4565
O
O
O
PGHN
b, c, h or b, d, h
or b, e, h
O
a
O
N
Ns
N
N
R1
35a PG = Ns
35b PG = Boc
35c PG = Cbz
34
c, f
c, g
OH
H
N
R2
H2N
N
O
O
N
fumarate
R1
9, 11-33
Scheme 1. Synthesis of (2S,4S,5S)-5-amino-6-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)-4-hydroxy-2-isopropylhexanamides. Reagents and conditions: (a) ketopipera-
zines, toluene, 110 °C; (b) P20 amines14c, cat. 2-hydroxypyridine, 80 °C; (c) PhSH, Cs2CO3, DMF, rt; (d) TFA, CH2Cl2, rt; (e) H2, cat. Pd-C, EtOH, rt; (f) Boc2O, Et3N, CH2Cl2, rt; (g)
CbzCl, Et3N, CH2Cl2, rt; (h) fumaric acid, MeOH, rt.
X
NHBoc
a
b
X
N
NHBoc
NHBoc
O
N
H
O
O
Br
38
36
37
O
NBoc
NH
c
e, f or e, g or f
2
2
N
N
X
X
39a X = 2-OBn
39b X = 2-OH
39c X = 2-Me
39d X = H
40a X = 2-O(CH2)3OMe
40b X = 2-O(CH2)2OMe
40c X = 2-OCH2OMe
40d X = 2-OMe
d
39e X = halogen(s)
40e X = 2-Me
40f X = H
40g X = halogen(s)
Scheme 2. Synthesis of ketopiperazines. Reagents and conditions: (a) anilines21, AcOH, NaBH(OAc)3, CH2Cl2, rt; (b) bromoacetyl bromide, DMA, 0 °C; (c) t-BuOK, THF, 0 °C; (d)
H2, cat. Pd-C, EtOAc, rt; (e) alkyl halides, Cs2CO3, DMF, rtꢀ100 °C; (f) TFA, CH2Cl2, rt; (g) TMSI, Et3N, CH2Cl2, 0 °C.
zines afforded lactones 35a in excellent yields. Subsequent N-ter-
minal amide bond formations with P20 amines14c under neat con-
ditions in the presence of 2-hydroxypyridine as catalyst,19
deprotection of the Ns group with PhSH and Cs2CO3,18 followed
by treatment with fumaric acid afforded the desired compounds
9 and 12 as fumarate salts. Compounds 11 and 13–33 were pre-
pared by a similar procedure after the N-Ns group of 35a have been
replaced with either the N-Cbz or the N-Boc protecting group. The
preparation of ketopiperazines are shown in Scheme 2. Reductive
amination of aldehyde 3620 with anilines,21 followed by acylation
with bromoacetyl bromide in DMA gave 38. Cyclisation reaction
by treatment of 38 with t-BuOK in THF afforded N-Boc-2,2-dimeth-
the corresponding amine intermediates (piperidine 42, ketopiper-
azines 46a, 46b and 48) used for the ring opening reaction with
aziridine 34 are outlined in the references.22,23
In conclusion, we have described the discovery and the SAR of
novel (2S,4S,5S)-5-amino-6-(4-phenylpiperazin-1-yl)-4-hydroxy-
2-isopropylhexanamides. Introduction of the 2,2-dimethyl-4-
phenylpiperazin-5-one P3–P1 scaffold resulted in a significant
improvement of in vitro potency without binding interactions to
the S3sp pocket. Compound 31 showed specificity over other aspar-
tyl proteases, and 18.5% oral bioavailability in cynomolgus mon-
key. From these encouraging results, we selected compound 31
as a new lead compound and have started further modifications
to acquire more promising compounds, which show excellent
in vivo efficacy in animal models. Further details of these efforts
will be reported in due time.
sp
ylketopiperazines 39a and 39c–e. The P3 aryl sidechains were
introduced by deprotonation of phenol 39b with Cs2CO3, followed
by addition of the corresponding alkyl halides. Finally, removal of
the N-Boc protecting group with TFA, or the combination of TMSI
and Et3N, delivered ketopiperazines 40. In addition, other com-
pounds listed in Table 1 were prepared following the same syn-
thetic route depicted in Scheme 1. Racemic form of aziridine 34
(rac-34) was used for the syntheses of rac-6–10. The syntheses of
Acknowledgements
We would like to thank Masumi Ueno and Kotaro Sugimoto for
their technical assistance.

4566
Y. Nakamura et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4561–4566
17. The stability in monkey liver microsomes was determined by
a high
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O
O
NBoc
NH
O
2
2
d
NBoc
a
3
N
3
N
HN
X
X
43
44a X= 2-OBn
44b X = 3-OBn
46a X = 2-O(CH2)3OMe
46b X = 3-O(CH2)3OMe
b, c
45a X = 2-O(CH2)3OMe
45b X = 3-O(CH2)3OMe
13. Nakamura, Y.; Ogawa, Y.; Suzuki, C.; Fujimoto, T.; Miyazaki, S.; Tamaki, K.;
Nishi, T.; Suemune, H. Heterocycles 2011, 83, 1587.
14. (a) Wood, J. M.; Maibaum, J.; Rahuel, J.; Grütter, M. G.; Cohen, N.-C.; Rasetti, V.;
Rügar, H.; Göschke, R.; Stutz, S.; Fuhrer, W.; Schilling, W.; Rigollier, P.;
Yamaguchi, Y.; Cumin, F.; Baum, H.-P.; Schnell, C. R.; Herold, P.; Mah, R.; Jensen,
C.; O’Brien, E.; Stanton, A.; Bedigian, M. P. Biochem. Biophys. Res. Commun. 2003,
308, 698; (b) Göschke, R.; Stutz, S.; Rasetti, V.; Cohen, N.-C.; Rahuel, J.; Rigollier,
P.; Baum, H.-P.; Forgiarini, P.; Schnell, C. R.; Wagner, T.; Gruetter, M. G.; Fuhrer,
W.; Schilling, W.; Cumin, F.; Wood, J. M.; Maibaum, J. J. Med. Chem. 2007, 50,
4818; (c) Maibaum, J.; Stutz, S.; Göschke, R.; Rigollier, P.; Yamaguchi, Y.;
Cumin, F.; Rahuel, J.; Baum, H.-P.; Cohen, N.-C.; Schnell, C. R.; Fuhrer, W.;
Gruetter, M. G.; Schilling, W.; Wood, J. M. J. Med. Chem. 2007, 50, 4832.
15. Assays were performed with the same procedure described in Ref. 10.
16. The X-ray crystallographic studies were accomplished according to the
procedure described in Ref. 7. Coordinates and statistics are available from
the PDB using accession code 3VSW (complex with compound 7) and 3VSX
(17).
O
O
MeO
O
NH
BnO
NBoc
e
b, c, d
44a
N
N
47
48
a
Reagents and conditions: (a) CuI, 2- or 3-benzyloxyiodo-benzene25, K3PO4, N,N’-
dimethylethylenediamine, DMF, 100 °C; (b) H2, cat Pd-C, EtOAc, rt; (c) 1-bromo-3-
methoxypropane, Cs2CO3, DMF, 100 °C; (d) TFA, CH2Cl2, rt; (e) LDA, MeI, THF, rt.
24. Gray, D. L.; Xu, W.; Campbell, B. M.; Dounay, A. B.; Barta, N.; Boroski, S.; Denny,
L.; Evans, L.; Stratman, N.; Probert, A. Bioorg. Med. Chem. Lett. 2009, 19, 6604.
25. (a) Portscheller, J. L.; Malinakova, H. C. Org. Lett. 2002, 4, 3679; (b) Jin, Y. L.;
Kim, S.; Kim, Y. S.; Kim, S.-A.; Kim, H. S. Tetrahedron Lett. 2008, 49, 6835.