Spirodiketopiperazine-based CCR5 antagonist: Discovery of an antiretroviral drug candidate

Article abstract of DOI:10.1016/j.bmcl.2010.12.109

Following the discovery that hydroxylated derivative 3 (Fig. 1) was one of the oxidative metabolites of the original lead 1, it was found that hydroxylated compound 4 possesses higher in vitro anti-HIV potency than the corresponding non-hydroxylated compo

Full text of DOI:10.1016/j.bmcl.2010.12.109

Bioorganic & Medicinal Chemistry Letters 21 (2011) 1141–1145
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Spirodiketopiperazine-based CCR5 antagonist: Discovery
of an antiretroviral drug candidate
Rena Nishizawa a, , Toshihiko Nishiyama a, Katsuya Hisaichi a, Chiaki Minamoto a, Naoki Matsunaga a,
⇑
Yoshikazu Takaoka a, Hisao Nakai a, Stephen Jenkinson c, Wieslaw M. Kazmierski c, Hideaki Tada b,
Kenji Sagawa b, Shiro Shibayama b, Daikichi Fukushima b, Kenji Maeda d,e, Hiroaki Mitsuya d,e
a Medicinal Chemistry Research Laboratory, Ono Pharmaceutical Co., Ltd, Shimamoto, Mishima, Osaka 618-8585, Japan
b Exploratory Research Laboratory, Ono Pharmaceutical Co., Ltd, Ibaraki 300-424, Japan
c GlaxoSmithKline Research and Development, Five Moore Drive, Research Triangle Park, NC 27709-3398, USA
d Department of Internal Medicine II, Kumamoto University School of Medicine, Kumamoto 860-0811, Japan
e Experimental Retrovirology Section, HIV & AIDS Malignancy Branch, NCI, National Institutes of Health, Bethesda, MD 20892, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Following the discovery that hydroxylated derivative 3 (Fig. 1) was one of the oxidative metabolites of the
original lead 1, it was found that hydroxylated compound 4 possesses higher in vitro anti-HIV potency
than the corresponding non-hydroxylated compound 2. Structural hybridation of 4 with the orally avail-
able analog 5 resulted in another orally-available spirodiketopiperazine CCR5 antagonist 6a that pos-
sesses more favorable pharmaceutical profile for use as a drug candidate.
Received 15 October 2010
Revised 20 December 2010
Accepted 22 December 2010
Available online 28 December 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
CCR5
Chemokine
Anti-HIV
Since the United States Food and Drug Administration (US FDA)
approval of the first antiretroviral drug in 1987, new agents have
been added to the list of treatment options for human immunode-
ficiency virus type-1 (HIV-1) infection. Due to the increased inci-
dence of drug-resistant viruses, there has been a growing need
for novel treatments of HIV-1 infections. Therefore, the identifica-
tion of new antiretroviral drugs that have unique mechanisms of
action remains an important therapeutic objective.1 In 1996, it
was revealed that one of the C–C chemokine receptors, CCR5, is uti-
lized by HIV-1 as one of the essential co-receptors and that the
endogenous ligand showed anti-HIV-1 activity in vitro.2 For such
reasons, CCR5 antagonists that inhibit viral entry into the host cell
are thought to be one of the most promising class of new antiviral
drugs.
Since these discoveries, many pharmaceutical companies and
academic institutions have been enthusiastically investigating no-
vel CCR5 antagonists.3 Thus far Maraviroc is currently the only ap-
proved CCR5 antagonist on the market for the treatment of HIV-1
infection. Due to its new mechanism of action, CCR5 antagonists
may be utilized in salvage therapy in patients who have become
resistant to one or multiple classes of antiretrovirals, in combina-
tion with other classes of active antiretroviral agents.
We have previously reported the discovery of spirodiketopiper-
azines 1 and 2 as structurally novel CCR5 antagonists (Fig. 1).4 Both
of these compounds showed potent anti-HIV activity, in vitro. After
the incubation of 1 with human liver microsomes, the hydroxyl-
ated analog of 10 position was identified as the biologically active
metabolite.5 Since the proposed structure of metabolite had two
chiral centers, we synthesized all four possible stereo-isomers as
their optically pure form from the corresponding b-hydroxylated
leucine to evaluate their biological activities. Compound 3, having
a
(3R,10R)-configuration, exhibited approximately 4.5-12-fold
higher potency than the other isomers in Ca assay. Based on the
observation of this unexpectedly improved antagonist activity of
compound 3, we applied this information to compound 2 which
showed more potent in vitro activity than compound 1. Thus, it
was found that the (3R, 10R)-hydroxylated compound 4 also exhib-
ited strong antagonist activity.5,6 Although the hydroxylated ana-
logs 3 and 4 could not improve the bioavailability in rodents5,
they showed some favorable pharmaceutical properties. For exam-
ple, 4 did not show any significant inhibition of CYP 3A4 up to
30
6.8) of 4 was significantly improved relative to the corresponding
non-hydroxylated analog (2: <0.2 g/mL; 4: 2.7 g/mL). Further
assessment and optimization led us to the discovery of the
lM (2: 9.3 lM of IC50). Furthermore, aqueous solubility (pH
l
l
⇑
Corresponding author. Tel.: +81 75 961 1151; fax: +81 75 962 9314.
E-mail address: r.nishizawa@ono.co.jp (R. Nishizawa).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.12.109

1142
R. Nishizawa et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1141–1145
CH3
O
3 (3R, 1'R)
CH3
O
HCl
N
R =
O
N
OH
1'
3
O
HCl
N
1
4 (3R, 1'R)
R =
N
R
N
H
2
O
3
5
4
CH3
N
R
H
HO2C
O
O
O
HCl
N
1 (3RS
R =
)
2 (3RS)
R =
N
3
N
H
5 (3S)
O
Figure 1. Lead compounds of CCR5 antagonists.
spirodiketopiperazine-based structure 5 as an orally-available
CCR5 antagonist.7 Based on the observation described above, we
synthesized and evaluated 6a, which was expected to have im-
proved potency and oral availability with favorable pharmaceutical
properties due of its hybrid structure possessing both of the fea-
tures derived from 4 and 5. The other possible stereoisomers 6b-
d were also synthesized and evaluated.
3R-isomer 6b and 3S-isomer 6d exhibited nearly equipotent activ-
ity. This specific SAR was consistent with the SAR of 4 and its three
stereoisomers.5
According to the results of the fusion assay, 6a showed nearly
two orders of magnitude more potency in the pIC50 values relative
to those of other three stereoisomers 6b–d. This lack of correlation
between anti-chemokine activity and anti-HIV activity has been
previously reported, and is attributed to the allosteric nature of
CCR5 inhibition.10 Such a discrepancy observed between the cal-
cium assay and the fusion assay was considered to be because of
the following reasons. The calcium assay (receptor antagonist
Test compounds 6a-d listed in Table 1 were synthesized as out-
lined in Scheme 1. As shown in Scheme 1, the Ugi four component
coupling reaction of N-benzylpiperizine-4-one, n-butyl amine, an
appropriate optically-active amino acid among 7a–d and
2-(4-morpholinyl)ethyl isonitrile followed by deprotection of
N-Boc group and cyclization under acetic acid condition afforded
the 9-N-benzyl spirodiketopiperazines is represented by the gen-
eral formula 8 in 60–90% yield from 7a–d. The stereochemical pur-
ity of the Ugi products was confirmed by NMR. Catalytic
hydrogenation of 8 followed by reductive 9-N-alkylation with
4-(4-formylphenoxy)benzoic acid resulted in 6a–d in 50–90%
yield. Optically-active amino acids 7a–d were prepared using
Sharpless asymmetric epoxidation as previously reported.8 The
synthetic procedures of amino acid 7a (2R, 3R) and 7c (2S, 3R)
are described as a representative example in Scheme 2. According
to the same procedure as described for preparation of 7a from 13a,
the amino acid 7d (2S, 3S) was synthesized from the enantiomer of
13a, which was prepared from 12 by Sharpless asymmetric epoxi-
dation using another enantiomeric diethyl tartrate. According to
the same procedure as described for the preparation of 7c from
13a, the amino acid 7b (2R, 3S) was prepared from the enantiomer
of 13a.
activity) was conducted using the natural ligand (MIP-1a), while
the fusion assay (inhibitory effect on HIV envelope glycoprotein-
mediated cell–cell fusion) was conducted using envelope
glycoprotein. To more extensively estimate the activity of these
compounds, the inhibition of virus entry mediated by membrane
fusion and/or the HIV replication inhibition should be evaluated
in addition to the receptor antagonist activity. The HIV replication
inhibition results are described further in the article.
Isomers 6a-d were investigated for their inhibitory activity on
cytochrome P450 (2C9, 2D6 and 3A4 isomers) as shown in
Table 2. For comparative purposes, the profiles of 1-5 were
included to demonstrate the improvement shown with 6a-d. The
initial leads 1 and 2 showed P450 inhibition on all the enzymes
tested, while the hydroxylated analogs 3 and 4 showed no
inhibition on 3A4 up to 30 lM. Analog 5 which also possessed
the p-carboxylic acid functional group still showed inhibitory
activity on 2C9 and 3A4, while it did not show inhibitory activity
on 2D6 up to 30
tial as a drug candidate did not show inhibitory activity on all the
tested enzymes up to 30 M. As described above, introduction of
lM. The analog 6a that possesses the best poten-
Compounds 6a–d listed in Table 1 were evaluated for their
inhibitory activities against calcium mobilization of human CCR5
l
over-expressed CHO cell (hCCR5/CHO) stimulated by MIP-1
a
(Ca
the hydrophilic functions such as hydroxyl and/or carboxylic acid
functions was effective to remove or reduce these inhibitory activ-
ities. Among the tested compounds, only (3R, 10S)-isomer 6b
showed inhibitory activity against 2C9. While this result was not
able to be explained rationally, (3R, 10S)-configuration was esti-
mated to have a tendency to show relatively more affinity to the
enzyme 2C9 than the other three configurations.
assay)6a and for their inhibitory activity of cell-cell fusion reaction
between target cells expressing CD4/CCR5 and effector cells
expressing the envelope protein of HIV-1.9
As shown in Table 1, we evaluated 6a-d to investigate the struc-
ture–activity relationship (SAR) of the four stereoisomers. In our
previous paper,5 we reported that the (3R, 10R)-isomer 4 was iden-
tified to show the most potent in vitro activities among the four
possible stereoisomers. Based on the SAR of 4 and its possible three
stereoisomers, 6a was predicted to show the most potent antago-
nistic activity. Unexpectedly, however, isomers 6a, 6b and 6d
showed nearly equipotent antagonistic activity, while 6c (3S, 10R)
showed nearly 10-fold less antagonistic activity. Regarding the
10R-isomers, the 3R-isomer 6a showed more potency than the
corresponding 3S-isomer 6c. Regarding the 10S-isomers, both the
The (3R, 10R)-configuration of 6a was identified as possessing
the most optimized stereochemistry regarding the biological
potency, while the p-carboxylic acid function was found to be
necessary for oral bioavailability, as illustrated by 5. For the simul-
taneous optimization of the biological potency and oral bioavail-
ability, the (3R, 10R)-configuration and the p-carboxylic acid
function are both needed, as indicated by the area under the curve
(AUC) values (6a > 6b–d) after oral dosing described in Table 3.

R. Nishizawa et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1141–1145
1143
Table 1
Activity profiles of stereoisomers 6a–d
Compound
Ca assay IC50 (nM)
Fusion assay pIC50
1
2
3
4
5
94
28
84
53
13
6.07
NDa
6.64
8.11
7.06
CH3
N
HO2C
O
O
O
O
O
O
O
O
6a(3R, 1’R)
34
8.25
6.74
6.42
6.35
OH
1'
3
N
N
N
N
N
H
O
CH3
C
HO2
6b(3R, 1’S)
44
OH
OH
OH
N
N
H
O
CH3
N
HO2C
6c(3S, 1’R)
470
N
H
O
CH3
N
HO2C
6d(3S, 1’S)
51
N
H
O
a
ND : Not determined.
CH3
CH3
O
O
HO2C
CH3
NH2
HO
Boc
OH
2
O
Ph
e
1
a, b, c
O
+
+
O
N
OH
N
N
H
N
OH
3
R
N
N
3
N
H
N
HCl
O
H
O
7a-d
8a-d R = Bn
9a-d R = H
d
6a-d
a (1R,2R)
)
)
)
b (1R,2S
c (1S,2R
d (1S,2S
Scheme 1. Synthesis of spirodiketopiperazines 6a–d. Reagents and conditions: (a) 2-(4-morpholinyl)-ethyl isonitrile, MeOH, 55 °C; (b) concd HCl, 55 °C; (c) AcOH/toluene,
80 °C; (d) H2, Pd(OH)2/C, EtOH, 50 °C, then 4 N HCl/AcOEt, 60–90% yield in four-steps; (e) 4-(4-formylphenoxy)benzoic acid, NaBH(OAc)3, AcOH, DMF and then 4 N HCl/AcOEt,
50–90% yield.
Analogs 6a-d were evaluated for their pharmacokinetics (PK)
values after their single dose oral administration and intravenous
administration in rats. These data are summarized in Table 3.
Among the four tested compounds, 6a showed the best oral expo-
sure (AUC = 3422 ng h/mL) and maximum plasma concentration
(Cmax = 2360 ng/mL). A marked improvement of the AUC value of
6a relative to the chemical lead 1 (Table 5) after oral dosing was
estimated to be due to the marked reduction of the clearance
(CL) and tissue distribution (Vss) after intravenous dosing. Thus,
stereochemistry of position-3 and position-10 of 6a (3R, 10R) was
thought to be involved as one of the factors for the improvement
of PK values as illustrated by the lower Cmax and AUC values after

1144
R. Nishizawa et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1141–1145
CO2H
CO2H
c
d
a
O
+
OH
OH
2
CO2R'
CHO
3
10 R' = H
12
13a
b
11 R' = Me
NHBn
NHBoc
CO2H
e, f, g
h
13a
13a
CO2H
OH
OH
14a
7a
OH
CO2R
NBn
CO2H
NBn
NHBoc
CO2H
m, n
i
j
l
NBn
O
O
O
O
OH
7c
O
O
14c
15c R = H
17c
k
16c R = Me
Scheme 2. Synthetic method of optically-active b-hydroxy-N-Boc-
a-amino acids 7a and 7c. Reagents and conditions: (a) piperidine, pyridine, 97%; (b) concd H2SO4, MeOH,
87%; (c) DIBAL, THF, 90%; (d) (ꢀ)-diethyl-
D
-tartrate, Ti(Oi-Pr)4, cumene hydroperoxide, MS4A, CH2Cl2, 85%; (e) SO3.pyridine, Et3N, DMSO; (f) 2-methyl-2-butene, NaClO2,
NaH2PO4, MeCN, H2O; (g) BnNH2, 5.0 M NaOH, H2O, 35% from 13; h) H2, Pd(OH)2/C, MeOH, then Boc2O, 1.0 M NaOH, 97%; (i) benzyl isocyanate, NaH, THF, 28%; (j) Jones
reagent, acetone; (k) TMS-diazomethane, diethyl ether, 62% from 14c; (l) KOH, EtOH, 98%; (m) 2.0 M KOH; (n) H2, Pd(OH)2/C then Boc2O, 84% from 17c.
Table 2
Table 4
P450 inhibition of 1–5 and 6a–d
In vitro metabolic stability, Caco2 permeability, and solubility of 6a–d
Compound
P450 inhibition IC50
2D6
(
lM)
Compound
% Remaininga
Caco2 ꢁ 10ꢀ6 (cm/s)
Solubilityd
(lM)
2C9
3A4
HLMb
RLMc
1
2
3
4
5.9
5.5
>30
3.7
8.8
>30
18
4.6
7.8
>30
9.8
>30
>30
>30
>30
>30
19.7
9.3
6a (3R, 10R)
6b (3R, 10S)
6c (3S, 10R)
6d (3S, 10S)
36
39
3.8
1.6
1.6
2.1
70
81
85
80
90.1
88.1
69.8
76.5
74.8
52.7
>30
>30
24.9
>30
>30
>30
>30
5
a
The data show the remaining% 15 min after incubating with the 0.5 mg/mL liver
microsomes.
6a
6b
6c
6d
b
Human liver microsomes
Rat liver microsomes
Kinetic solubility
>30
>30
c
d
Table 5
oral dosing of 6b (3R, 10S), 6c (3S, 10R), and 6d (3S, 10S). Stability of
these test compounds in rat liver microsomes was investigated but
all isomers 6a-d did not show significant differences between each
other in in vitro metabolic stability, Caco2 permeability, and solu-
bility, as shown in Table 4. In vitro metabolic stability and in vivo
clearance of these test compounds did not show a strong relation-
ship. Therefore, one cannot rule out other clearance processes in
addition to metabolic ones to explain the mismatch in Cmax/AUC
across the 4 isomers. The differences in their susceptibility to the
systemic metabolism, transporter recognition and/or the changes
in Vss may suggest additional processes.
Anti-HIV activity of the representative compounds
Compound
Anti-HIV-1 activity IC50 (nM)a
HIV-1Ba-L (R5)
HIV-1MM (R5MDR
0.6 0.2
)
6a
0.4 0.3
28 32
TAK-779
SCH-351125
Zidovudineb
Nelfinavirc
14
3
8
0.5
4
7
2
4
8
250 98
>1000
12
a
b
c
IC50 values are based on the inhibition of HIV p24 antigen expression in PBMC.
Zidovudine is a reverse transcriptase inhibitor.
Nerfinavir is a HIV-1 protease inhibitor
Table 3
Pharmacokinetic profiles of 6a–d
Compound
10 mg/kg, po
3 mg/kg, iv
Cmax (ng/mL)
T1/2 (min)
AUC (ng h/mL)
BA (%)
AUC (ng h/mL)
T1/2 (min)
CL (mL/min/kg)
Vss (mL/kg)
1
2
5
33.3a
5.6a
2400
2360
70
75.7
103
48.4
120
35.2
14.4
19.2
96.7a
24.8a
10532
3422
67.5
1.3
1.9
34
372
400
13
137
113
16
11.3
NDb
NDb
50.9
2349
2542
145
19.9
11.1
21.8
NDb
NDb
16.2
3091
4402
NDb
NDb
988
6a (3R, 10R)
6b (3R, 10S)
6c (3S, 10R)
6d (3S, 10S)
23
132
NDb
NDb
6.5
NDb
NDb
836
280
260
126
213
a
Cmax and AUC are normalized to a dose of 10 mg/kg.
ND: Not determined.
b

R. Nishizawa et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1141–1145
1145
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