Discovery of DS-8108b, a novel orally bioavailable renin inhibitor

Article abstract of DOI:10.1021/ml300168e

A novel orally bioavailable renin inhibitor, DS-8108b (5), showing potent renin inhibitory activity and excellent in vivo efficacy is described. We report herein the synthesis and pharmacological effects of 5 including renin inhibitory activity in vitro, suppressive effects of ex vivo plasma renin activity (PRA) in cynomolgus monkey, pharmacokinetic data, and blood pressure-lowering effects in an animal model. Compound 5 demonstrated inhibitory activities toward human renin (IC₅₀ = 0.9 nM) and human and monkey PRA (IC₅₀ = 1.9 and 6.3 nM, respectively). Oral administration of single doses of 3 and 10 mg/kg of 5 in cynomolgus monkey on pretreatment with furosemide led to dose-dependent significant reductions in ex vivo PRA and sustained lowering of mean arterial blood pressure for more than 12 h.

Full text of DOI:10.1021/ml300168e

Letter
pubs.acs.org/acsmedchemlett
Discovery of DS-8108b, a Novel Orally Bioavailable Renin Inhibitor
Yuji Nakamura,† Teppei Fujimoto,† Yasuyuki Ogawa,† Chie Sugita,† Shojiro Miyazaki,†
Kazuhiko Tamaki,† Mizuki Takahashi,‡ Yumi Matsui,‡ Takahiro Nagayama,§ Kenichi Manabe,§
Makoto Mizuno,∥ Noriko Masubuchi,⊥ Katsuyoshi Chiba,# and Takahide Nishi*,†
‡
†Lead Discovery & Optimization Research Laboratories I, Lead Discovery & Optimization Research Laboratories II,
∥
⊥
§Cardiovascular-Metabolics Research Laboratories, Biological Research Laboratories, Drug Metabolism & Pharmacokinetics
#
Research Laboratories, and Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku,
Tokyo 140-8710, Japan
S
* Supporting Information
ABSTRACT: A novel orally bioavailable renin inhibitor, DS-8108b (5), showing
potent renin inhibitory activity and excellent in vivo efficacy is described. We report
herein the synthesis and pharmacological effects of 5 including renin inhibitory
activity in vitro, suppressive effects of ex vivo plasma renin activity (PRA) in
cynomolgus monkey, pharmacokinetic data, and blood pressure-lowering effects in
an animal model. Compound 5 demonstrated inhibitory activities toward human
renin (IC50 = 0.9 nM) and human and monkey PRA (IC50 = 1.9 and 6.3 nM,
respectively). Oral administration of single doses of 3 and 10 mg/kg of 5 in
cynomolgus monkey on pretreatment with furosemide led to dose-dependent
significant reductions in ex vivo PRA and sustained lowering of mean arterial blood pressure for more than 12 h.
KEYWORDS: renin inhibitor, hypertension, plasma renin activity, 4-aminoadamantan-1-ol
significant research investments from the pharmaceutical
he renin−angiotensin−aldosterone system (RAAS) plays
Tan important role in regulating blood pressure and industry directed toward the discovery of renin inhibitors
suitable for clinical development,12,13 only aliskiren has been
launched to the market for the treatment of hypertension to
date.14,15
extracellular fluid volume.1,2 Chronic stimulation of the RAAS
leads to tissue inflammation and fibrosis with end organ
dysfunction, particularly of the kidney.3,4 The aspartyl protease
renin, secreted from kidneys, is the first and rate-limiting
enzyme of the RAAS system and cleaves angiotensinogen at the
N terminus to form the decapeptide angiotensin (Ang) I. Ang I
is further converted by angiotensin converting enzyme (ACE)
to give an octapeptide, Ang II, which binds to the angiotensin
receptor type 1 (AT1), leading to vasoconstriction, chronic
stimulation, inflammation, and fibrosis. While two major classes
of RAAS blockers, ACE inhibitors and AT1 receptor blockers
(ARBs), are already on the market, it is expected that a direct
renin inhibitor would be valuable as it would not only become
an ideal antihypertensive agent for end organ protection but
also cause fewer mechanism-based adverse events than ACE
inhibitors and ARBs.5−7
Although renin inhibitors have been considered to be
desirable antihypertensive drugs, identification of orally active,
low molecular weight compounds have proven to be a very
challenging task. During the 1980s, all of the first generation
renin inhibitors were peptides or peptidomimetics that
incorporated peptide hydrolysis transition state isosteres.
However, because of their poor oral bioavailability, none of
these inhibitors was successfully developed as a drug.8
Beginning in the middle of the 1990s, several novel nonpeptidic
renin inhibitors were reported and have entered human clinical
trials, such as aliskiren hemifumarate (1),9 ACT-077825 (MK-
8141) (2),10 and VTP-27999 (3)11 (Figure 1). Despite
We recently discovered a novel class of nonpeptidic renin
inhibitors such as 4 characterized by a 2,2-dimethyl-4-
phenylpiperazin-5-one moiety as the P3−P1 pharmacophore.
Inhibitor 4 showed an IC50 value of 2.0 nM in purified human
renin and 18.5% oral bioavailability in cynomolgus monkey.16
On the basis of these encouraging results, we selected 4 as a
new lead compound and started further modifications to
acquire more promising compounds. In earlier work with
related compounds, our approach to improve efficacy and oral
bioavailability was to introduce a lipophilic moiety into the
molecule. However, increasing the lipophilicity of the
compounds caused several drawbacks such as interactions
with CYPs and cardiac safety problems. These problems also
have been reported by other research groups.17−19 Thus, we
replaced the N-terminal butyl side chain of 4 with various
substituents incorporating additional polar functionalities to
reduce the above undesirable concerns while retaining excellent
efficacy. As a result, the introduction of trans-4-amino-
adamantan-1-ol to the N-terminal portion led to the
identification of clinical candidate DS-8108b (5) ((2R,4S,5S)-
5-amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-
Received: June 26, 2012
Accepted: August 18, 2012
Published: August 18, 2012
© 2012 American Chemical Society
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ACS Medicinal Chemistry Letters
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Figure 1. Structures of renin inhibitors.
a
Scheme 1
a
Reagents and conditions: (a) NaN(TMS)2, (E)-BnOCH2CHCHCH2Br, THF, −78 to −40 °C, 81%. (b) LiOH, 30% aqueous H2O2, THF−H2O
(3:1), 0 °C to rt. (c) 1,2:4,5-Di-O-isopropylidene-β-D-erythro-2,3-hexodiulo-2,6-pyranose, Oxone, K2CO3, aqueous Na2(EDTA), Na2B4O7·10H2O,
dimethoxymethane−MeCN (2:1), 0 °C, 70% (two steps). (d) MsCl, Et3N, CH2Cl2, 0 °C, 96%. (e) NaN3, DMPU, 60 °C, 93%. (f) Cat. Pd−C, H2,
HCl, EtOH, rt. (g) (i) NsCl, Et3N, THF−H2O (10:1), rt; (ii) crystallization in diisopropylether−AcOEt (1:2), 59% (two steps). (h) DEAD, PPh3,
THF, 0 °C, 92%. (i) Toluene, 110 °C, 96%. (j) PhSH, Cs2CO3, MeCN, rt, 90%. (k) Boc2O, NaHCO3, AcOEt−H2O (1:1), 96%. (l) trans-4-
Aminoadamantan-1-ol, cat. 2-hydroxypyridine, 90 °C, 72%. (m) TFA, CH2Cl2, rt. (n) (i) Fumaric acid, MeOH, rt; (ii) crystallization in 95% aqueous
MeCN and 98% aqueous AcOEt (77%, three steps).
yl]-2-ethyl-4-hydroxy-N-[(2s,5s)-5-hydroxyadamantan-2-yl]-
hexanamide monofumarate dihydrate).
mediate aziridine 11 was prepared according to a similar
procedure reported recently.21 Asymmetric alkylation of 6 with
benzyl (2E)-4-bromobut-2-en-1-yl ether22 to construct the C-2
chiral center of 5 proceeded smoothly, and the oxazolidinone
group was removed with LiOH and 30% aqueous H2O2 to
afford the carboxylic acid (2R,4E)-7 in good yield. To construct
chirality centers at the C-4 and C-5 of 5, Shi's asymmetric
epoxidation method was employed.23 Epoxidation of (2R,4E)-7
followed by one-pot intramolecular lactonization produced
We report herein the synthesis and pharmacological effects of
5 including its renin inhibitory activity in vitro, ex vivo PRA
suppressive effects in monkey, and the blood pressure-lowering
effects in an animal model and also report the pharmacokinetic
(PK) profiles in monkey.
The synthetic route of DS-8108b (5) is shown in Scheme 1.
The N-(2-nitrobenzenesulfonyl) (Ns)20 protected key inter-
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ACS Medicinal Chemistry Letters
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alcohol 8 as a mixture of stereoisomers (ca. 97:3). The slow
addition of Oxone and K2CO3 in aqueous Na2(EDTA) solution
over a period of 4 h to the reaction mixture of 7 and 1,2:4,5-di-
O-isopropylidene-β-D-erythro-2,3-hexodiulo-2,6-pyranose (1
equiv) was necessary to complete the reaction. Mesylation of
8 with MsCl and triethylamine and subsequent SN2 substitution
of the methanesulfonyloxy group with an azide group was
accomplished by treatment with sodium azide in 1,3-dimethyl-
3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) to obtain 9.
Then, hydrogenation of 9 in the presence of HCl and the
subsequent reaction with 2-nitrobenzenesulfonyl chloride
(NsCl)20 under the Schotten−Baumann conditions, followed
by crystallization gave N-Ns alcohol 10 as a single diastereomer
in 59% yield from 9. N-Ns-protected 11 was formed by the
Mitsunobu reaction of 10 with diethyl azodicarboxylate
(DEAD) and Ph3P in 92% yield. The ring opening of aziridine
11 with 4-(2-chlorophenyl)-2,2-dimethylpiperazin-2-one (12)16
proceeded smoothly in toluene at 110 °C to afford lactone 13
in excellent yield. After replacement of the Ns group with the
Boc group, sequential N-terminal amide bond formation with
trans-4-aminoadamantan-1-ol under neat conditions at 90 °C in
the presence of 2-hydroxypyridine as a catalyst,24 deprotection
of the Boc group with trifluoroacetic acid (TFA) in CH2Cl2,
and treatment with fumaric acid afforded the desired DS-8108b
(5).
Table 1. In Vitro Renin Inhibition
a,b
IC50 (nM)
Figure 2. X-ray crystal structure of 5 in complex with human renin
(PDB code: 3VUC). Water molecules are shown as red dots. (a)
Overview, (b) S1−S3 region, and (c) S2′ region.
compd
human renin human PRA monkey PRA
aliskiren hemifumarate (1)
DS-8108b (5)
1.5
0.9
2.9
1.9
8.0
6.3
a
b
Assay protocols are provided in the Supporting Information. Assay
and interacts with Phe112 (Figure 2b). To our knowledge, this
is the first example of a halogen-π interaction reported for
aspartyl protease inhibitors. The carboxamide oxygen of the
2,2-dimethyl-4-phenylpiperazin-5-one moiety participates in a
hydrogen bond to Thr77. In addition, the hydroxyl group of
adamantane located in the S2′ pocket forms a hydrogen-
bonding network involving the backbone atoms of Thr72,
Arg74, and a water molecule (Figure 2c).
In another series of experiments, the ex vivo PRA suppressive
effects of 5 were investigated in cynomolgus monkey (Figure
3). Vehicle or 1, 3, and 10 mg/kg of 5 were orally administered
to cynomolgus monkey after pretreatment with furosemide.
Compound 5 showed PRA suppressive effects in a dose-
dependent manner at a dose of 1, 3, and 10 mg/kg, and more
than 65% of the PRA suppressive effects as compared with the
predose values were sustained over a period of 24 h for the 3
and 10 mg/kg groups. Thus, as compared with aliskiren
hemifumarate (data not shown), 5 demonstrated at least a three
times more potent PRA suppressive effect in cynomolgus
monkey at either the dose or the exposure level.
results are the average of at least two replicates.
Inhibitory activities of 5 toward human and cynomolgus
monkey renin are shown in Table 1. Aliskiren hemifumarate
(1) was included for comparison. Compound 5 demonstrated
potent inhibitory activity against human renin (IC50 = 0.9 nM),
comparable to that of aliskiren hemifumarate (IC50 = 1.5 nM).
Inhibitory effects on human and monkey plasma renin activity
(PRA) were also evaluated, and the IC50 values were 1.9 and
6.3 nM, respectively. In addition, 5 showed excellent selectivity
for renin over four other aspartyl proteases: human cathepsin
D, cathepsin E, pepsin, and HIV protease (IC50 = >10 μM),
and 5 also exhibited relatively weak inhibitory activities against
CYP enzymes and against a panel of 68 receptors, ion channels,
and enzymes with IC50 values >10 μM.25 Furthermore, 5 did
not affect the hERG and hNav 1.5 channel currents at a
concentration of 100 μM. Compound 5 was nonmutagenic in
the Ames assay when tested in either the presence or the
absence of S9 mix.
The X-ray crystal structure of 5 bound to human renin was
obtained (PDB code: 3VUC; Figure 2). The general binding
mode and specific interactions observed in the complex were as
expected based on the previously published X-ray crystal
structure of compound 4 (PDB code: 3VSX).16 Both X-ray
crystal structures of 4 and 5 in complex with renin provided
evidence that their P3 phenyl groups of compound 4 and 5
penetrate deeper into the S3 pocket than the phenyl ring of
Next, the antihypertensive efficacy of 5 was investigated in
cynomolgus monkey (Figure 4). Vehicle or 1, 3, and 10 mg/kg
of 5 were orally administered. Compound 5 showed significant
reduction in mean arterial blood pressure (MAP) in a dose-
dependent manner sustained over a period of at least 12 h.
The PK of 5 was evaluated in cynomolgus monkey. The PK
parameters after a single oral administration are shown in Table
2. The Cmax at doses of 3 and 10 mg/kg in monkey was 102 and
399 ng/mL, and the tmax was 3.0 and 2.3 h postdose,
respectively. The terminal half-life (t1/2) values in monkey at
sp
aliskiren and that both compounds do not utilize the S3sp
pocket. The chloro atom points toward the opposite site of S3
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ACS Medicinal Chemistry Letters
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Figure 3. Ex vivo PRA suppressive effects of DS-8108b (5) and aliskiren hemifumarate (1) in cynomolgus monkey on pretreatment with furosemide.
Note that vehicle (1% MC solution, white circle); 1 (light blue square), 3 (blue circle), and 10 mg/kg (dark blue triangle) of 5; and 3 (red times
sign) and 10 mg/kg (dark red tilted square) of 1 were orally administered to cynomolgus monkey after pretreatment with furosemide. PRA was
measured 1, 2, 4, 8, and 24 h after oral administration. Assay protocols are provided in the Supporting Information.
Figure 4. MAP responses to DS-8108b (5) in cynomolgus monkey on pretreatment with furosemide. Note that vehicle (1% MC solution, white
circle) and 1 (light blue square), 3 (blue circle), and 10 mg/kg (dark blue triangle) of 5 were orally administered to cynomolgus monkey. Data are
expressed as means SEMs. Assay protocols are provided in the Supporting Information.
Table 2. PK Parameters of DS-8108b (5) in Cynomolgus Monkey
dose (mg/kg)
Cmax (ng/mL)
tmax (h)
AUC0−t (ng h/mL)
t1/2 (h)
F (%)
CL (mL/min/kg)
3.59 1.74
Vss (L/kg)
a
3
102 60
3.0 1.7
685 452
15500 8200
2880 1710
5.1 0.7
7.8 2.6
5.4 0.7
4.1 0.6
b
3
1.12 0.52
a
10
399 177
2.3 1.5
5.3 1.0
a
b
po administration (n = 3). iv administration (n = 3).
oral doses of 3 and 10 mg/kg and an intravenous dose of 3 mg/
kg were 5.1, 5.4, and 7.8 h, respectively. The oral bioavailability
at doses of 3 and 10 mg/kg was 4.1 and 5.3%, respectively. The
low bioavailability of 5 in monkey is similar to that of aliskiren
hemifumarate (1) (data not shown).
Finally, we evaluated 5 in a cardiac safety study in
telemetered cynomolgus monkey. After administration of a
single oral dose of 1000 mg/kg of 5, the QRS width and QTc
interval over 24 h oral postdose were not impacted. These data
support that the potential cardiac toxicity risk of compound 5 is
considered to be low.
In summary, we present DS-8108b (5), a structurally novel
renin inhibitor possessing potent and selective renin inhibitory
activity with a profile suitable for further development. Oral
administration of single doses of 3 and 10 mg/kg of 5 in
cynomolgus monkey after pretreatment with furosemide
elicited sustained reductions in PRA and MAP in a dose-
dependent manner.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details for the synthesis and characterization of
DS-8108b (5), biological assays, animal studies, and crystallog-
raphy procedures. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Tel: +81-3-3492-3131. Fax: +81-3-5436-8563. E-mail: nishi.
takahide.xw@daiichisankyo.co.jp.
■
Author Contributions
Y.N., T.F., Y.O., C.S., S.M., K.T., and T.N. contributed to the
design and synthesis of DS-8108b (5); M.T. and Y.M.
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ACS Medicinal Chemistry Letters
Letter
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Renin Inhibitors as a New Therapy for Hypertension. J. Med. Chem.
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contributed to the X-ray crystal structures; T.N., K.M., and
M.M. contributed to the in vitro, ex vivo, and in vivo studies;
N.M. contributed to the PK studies; and K.C. contributed to
the cardiac study in cynomolgus monkey.
(13) Hershey, J. C.; Steiner, B.; Fischli, W.; Feuerstein, G. Renin
inhibitors: An antihypertensive strategy on the verge of reality. Drug
Discovery Today: Ther. Strategies 2005, 2, 181−185.
Notes
(14) Maibaum, J.; Stutz, S.; Goschke, R.; Rigollier, P.; Yamaguchi, Y.;
̈
The authors declare no competing financial interest.
Cumin, F.; Rahuel, J.; Baum, H.-P.; Cohen, N.-C.; Schnell, C. R.;
Fuhrer, W.; Gruetter, M. G.; Schilling, W.; Wood, J. M. Structural
Modification of the P2’ Position of 2,7-Dialkyl-Substituted 5(S)-
Amino-4(S)-hydroxy-8-phenyl-octanecarboxamides: The Discovery of
Aliskiren, a Potent Nonpeptide Human Renin Inhibitor Active after
Once Daily Dosing in Marmosets. J. Med. Chem. 2007, 50, 4832−
4844.
(15) Jensen, C.; Herold, P.; Brunner, H. R. Aliskiren: the first renin
inhibitor for clinical treatment. Nat. Rev. Drug Discovery 2008, 7, 399−
410.
(16) Nakamura, Y.; Sugita, C.; Meguro, M.; Miyazaki, S.; Tamaki, K.;
Takahashi, M.; Nagai, Y.; Nagayama, T.; Kato, M.; Suemune, H.;
Nishi, T. Design and Optimization of Novel (2S,4S,5S)-5-Amino-6-
(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)-4-hydroxy-2-isopropyl-
hexanamides as Renin Inhibitors. Bioorg. Med. Chem. Lett. 2012, 22,
4561−4566.
ACKNOWLEDGMENTS
■
We thank Dr. Hidenori Namiki, Masayoshi Asano, Akiyoshi
Mochizuki, Dr. Akifumi Kurata, Dr. Mikio Kato, Masumi Ueno,
Dr. Shinichi Inoue, Yoko Nagai, Dr. Jun Hirao, and Dr.
Naoyuki Maeda for their technical assistance and helpful
discussions. We also thank Prof. Soichi Wakatsuki of the
Institute of Materials Structure Science and the staff at the
Photon Factory for their assistance in the use of the
synchrotron beamline.
ABBREVIATIONS
■
TMS, trimethylsilyl; DEAD, diethyl azodicarboxylate; DMPU,
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; TFA, tri-
fluoroacetic acid
(17) Powell, N. A.; Ciske, F. L.; Cai, C.; Holsworth, D. D.; Mennen,
K.; Huis, C. A. V.; Jalaie, M.; Day, J.; Mastronardi, M.; McConnell, P.;
Mochalkin, I.; Zhang, E.; Ryan, M. J.; Bryant, J.; Collard, W.; Ferreira,
S.; Gu, C.; Collins, R.; Edmunds, J. J. Rational design of 6-(2,4-
diaminopyrimidinyl)-1,4-benzoxazin-3-ones as small molecule renin
inhibitors. Bioorg. Med. Chem. 2007, 15, 5912−5949.
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