Syntheses and biological evaluation of 5-(piperidin-1-yl)-3-phenyl- pentylsulfones as CCR5 antagonists

Article abstract of DOI:10.1016/j.bmcl.2004.03.112

Cellular proliferation of HIV-1 requires the cooperative assistance of both the CCR5 and CD4 receptors. Our medicinal chemistry efforts in this area have resulted in the identification of N-alkyl piperidine sulfones as CCR5 antagonists. These compounds display potent binding and show antiviral properties in HIV-1 spread cell-based assays.

Full text of DOI:10.1016/j.bmcl.2004.03.112

Bioorganic & Medicinal Chemistry Letters 14 (2004) 3589–3593
Syntheses and biological evaluation of 5-(piperidin-1-yl)-3-phenyl-
pentylsulfones as CCR5 antagonists
K. Shankaran,a,* Karla L. Donnelly,a Shrenik K. Shah,a Charles G. Caldwell,a Ping Chen,a
Paul E. Finke,a Bryan Oates,a Malcolm MacCoss,a Sander G. Mills,a Julie A. DeMartino,b
Sandra L. Gould,b Lorraine Malkowitz,b Salvatore J. Siciliano,b Martin S. Springer,b
Gloria Kwei,c Anthony Carella,c Gwen Carver,c Renee Danzeisen,c Daria Hazuda,c
Karen Holmes,c Joseph Kessler,c Janet Lineberger,c Michael D. Miller,c Emilio A. Eminic
and William A. Schleifc
aDepartment of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
bDepartment of Immunology Research, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
cDepartment of Antiviral Research, Merck Research Laboratories, West Point, PA 19486, USA
Received 11 February 2004; accepted 29 March 2004
Available online
Abstract—Cellular proliferation of HIV-1 requires the cooperative assistance of both the CCR5 and CD4 receptors. Our medicinal
chemistry efforts in this area have resulted in the identification of N-alkyl piperidine sulfones as CCR5 antagonists. These com-
pounds display potent binding and show antiviral properties in HIV-1 spread cell-based assays.
ꢀ 2004 Published by Elsevier Ltd.
1. Introduction
CXCR4 were identified as coreceptors along with CD4
for the entry of HIV into macrophages and T-cells.3
Subsequently it was discovered that certain individuals
homozygous for a 32-base pair deletion in the gene for
CCR5 show no expression of this receptor on cell sur-
faces and are highly resistant to HIV infection.4 HIV-
infected individuals heterozygous for this variation show
delayed progression to clinical AIDS.5 These observa-
tions provided compelling evidence that a suitable small
molecule CCR5 antagonist might have potential in the
therapeutic treatment of HIV infection.6
The plethora of drugs introduced during the past decade
to confront the AIDS crisis have resulted in an im-
proved quality of life for many individuals. Despite
these impressive gains, the disease, after stabilizing in
the US, is on the rise again with increasing numbers of
people infected with drug resistant stains of the virus.
Thus new therapeutic options, which tackle the repli-
cation of this insidious virus in novel ways are highly
desirable.
Earlier work with HIV-1 has established that the virus
uses CD4 as the primary receptor for cell entry. How-
ever, it was also recognized that while the CD4 receptor
was necessary, it was not sufficient for HIV-entry and a
secondary receptor was also involved. In 1995 it
became clear that the chemokines MIP-1a, MIP-1b, and
RANTES were active in suppressing of growth of HIV-1
in immune cells.1;2 The following year, CCR5 and
Toward this end, medicinal chemistry efforts aimed at
the development of CCR5 antagonists have resulted in
several publications from this and other laboratories.7
N-methylsulfonamides 1 and 2 along with related ana-
logs, are potent CCR5 antagonists displaying antiviral
activities7b;h in a cell-based assay. The amide 2, our lead
compound of interest in the present investigation,
showed low serum levels following an oral dosing in
dog.7h We reasoned that perhaps the replacement of the
sulfonamide group of 1 by the sulfone functionality, as
shown in 3 (Fig. 1), might lead to analogs with enhanced
metabolic stability. This communication details the
* Corresponding author. Tel.: +1-732-5943979; fax: +1-732-5943007;
e-mail: kothandaraman_shankaran@merck.com
0960-894X/$ - see front matter ꢀ 2004 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2004.03.112

3590
K. Shankaran et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3589–3593
Ph CH3
CH3
Ph CH3
N
N
O
N
SO2Ph
a
b
N
SO2Ph
BnO
N
Me
O
11
O
X S
Me
Et
O
OH
Me
O
12
O
2
1 (X = SO, SO2)
13
Me
Ph CH3
e
O
N
SO2Ph
N
SO2Ph
R4
R3
O
N
R2R1N
16
3
Me
OH
c, d
O2N
14
Figure 1.
Me
e
O
N
SO2Ph
O
N
preparation, SAR, and biological profile of such ana-
logs.
17
O2N
15
Me OH
Scheme 2. Reagents and conditions: (a) PhI, Et3N, Pd(PPh3)4, 80 ꢁC;
(b) DIBAL, THF, )78 ꢁC, and then PPh3Me/n-BuLi, )78 ꢁC to rt; (c)
DEAD, PPh3, p-nitrobenzoic acid, benzene, rt; (d) K2CO3, CH3OH,
rt; (e) Scheme 1 and steps c–f.
2. Chemistry
General routes for the synthesis of sulfones are shown in
Scheme 1. A smooth 1,4-addition of allyltrimethylsilane
to enone 4 gave 5.8 Ketone 5 was reduced to give a
mixture of alcohols that in a subsequent step was
transformed to the mesylate 6. The mesylate 6 under-
went a facile nucleophilic displacement by thiophenol to
afford the sulfide 7. The vinyl group in sulfide 7 was then
transformed to aldehyde 8 in a two step oxidative se-
quences that initially involved the transformation of the
sulfide to the sulfone, followed by ozonolysis of the
double bond to give 8. Reductive amination9 of 8 with
select amines (9) furnished the sulfones 10 as a mixture
of diastereomers.
one-pot reaction that initially involved DIBAL reduc-
tion of 12 to the intermediate lactol 13, which subse-
quently underwent a Wittig reaction to afford 14. To
access the other diastereomer, 15, we carried out an
inversion at the carbinol carbon via Mitsunobu reac-
tion12 on 14 to give a p-nitrobenzoyl ester that was
subjected to saponification to give 15. Eventual trans-
formation of 14 and 15 to the chiral sulfones 16 and 17
was analogous to the transformation of 6 to 10 de-
scribed in Scheme 1.
A similar sequence starting from the enantiomeric lac-
tone 1813 and following the protocol described for 16
and 17 in Scheme 2, produced sulfones 19 and 20, shown
below.
The synthesis of sulfones described above generated
stereochemical mixtures, which were not separated be-
fore initial screening in the CCR5 binding assay. Mix-
tures, which showed good activity were prepared in
stereochemically pure form as shown in Scheme 2. In
this route, the palladium-catalyzed Michael addition of
iodobenzene to the known chiral lactone 1110 gave
exclusively 12.11 During this reaction it was expected
that the addition of the phenyl group to the double bond
would be from the side opposite to the methyl group.
The lactone 12 was transformed to the carbinol 14 in a
Me
O
N
SO2Ph
O
N
19
Scheme 2
O2N
Me
O
O
and
18
Me
O
N
SO2Ph
O
N
20
O2N
R1
O
O
OMs
R2
a
b, c
R2
R2
R1
R1
5
6
4
Finally, other miscellaneous sulfone analogs described
in this communication that were necessary to complete
the SAR were prepared from other sulfone intermedi-
ates via known chemistry.14
O
SO2Ph
R2
SPh
R2
d
e, f
R1
R1
8
7
O
NH
R2
O
N
R3
O
N
SO2Ph
R1
9
R4
3. Results and discussion
O
N
R3
10
R4
g
The synthesized compounds were screened for CCR5
binding affinity employing the 125I-MIP-1a binding
assay.15 The initial IC50 data for the compounds shown
below (10a, 21, 22, and 23) clearly indicated to us that
the carbamate-based sulfone analog (10a) displayed
potency that was several magnitudes better than that of
R1 = H, Me, R2 = H, Me, Et, R3 = Et, allyl, R4 = H, NO2
Scheme 1. Reagents and conditions: (a) allyltrimethylsilane, TiCl4,
CH2Cl2; (b) NaBH4, MeOH; (c) MsCl, NEt3, CH2Cl2; (d) PhSH, CsF,
DMF; (e) H2O2, AcOH; (f) O3, MeOH/CH2Cl2 at )78 ꢁC, and then
PPh3 to rt; (g) Na(OAc)3BH, CH2Cl2.

K. Shankaran et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3589–3593
3591
Table 2. CCR5 binding activity of miscellaneous sulfonesa
the others. The sulfones with the 3-phenylpropyl (21)
and phenyl (22) piperidines showed weak affinity for the
receptor. The results for 21 and 22 are to be contrasted
with those obtained for the pyrrolidine and N-sulfon-
amide based CCR5 antagonists, wherein the presence of
such a subunit resulted in analogs with superb binding
potency.7b;h
R1
N
R4
O
R3
R2
N
O
O2N
Entry
R1
R2
R3
R4
IC50 (nM)b
10h
10i
Me
Me
Me
Me
H
Me
H
Me
H
SO2Ph
SO2Me
SO2Et
SO2Pri
COPh
11
6
Me
Me
N
O
N
SO2Ph
SO2Ph
1
3
10k
10l
H
H
6
O
N
OH
21 (64% @ 10 µM)
H
H
5
15
10m
H
H
10a (IC50 = 8.6 nM)
a The examples shown are diastereomeric mixtures and prepared
according to Scheme 1.
b The IC50 results are an average of three independent titrations having
calculated standard error below 15% and the variability was generally
3-fold.
Me
O
N
O
Ph
N
SO2Ph
O
N
22 (45% @ 10 µM)
23 ( 72% @ 1 µM)
with an additional methyl group at C-3, is equipotent to
10a. The sulfone analog 10d, lacking the methyl sub-
stituent at C-1, displayed a 4-fold loss of potency com-
pared to 10a. These results clearly suggest that a small
alkyl group at C-1 is highly desirable. An impressive 12-
fold gain in binding potency was further achieved for the
sulfone analogs upon replacement of the O-benzyl/N-
ethyl carbamate subunit (10b) with O-(4-nitro-benzyl)/
N-allyl (10e). This was also seen for the analogs 10f and
10g. Analogous results have been observed for the N-
sulfonamide compounds7h reported from these labora-
tories.
Ethers such as 23 that still retained the carbamate unit
(as in 10a) but lacked the sulfone moiety were not active.
These results clearly underscore the beneficial effect of
both the sulfonyl and carbamate group in the present
lead class.
Further efforts in this lead class probed ways to modify
the sulfone 10a. This involved the placement of alkyl
substituents at C-1/C-3 of n-pentyl backbone, change in
carbamate substitution on the piperidine ring and finally
the replacement of the phenylsulfone moiety by other
sulfones. The results from the binding assay for the
synthesized analogs are compared with 10a and are
displayed in Tables 1 and 2.
Since the combination of the 4-nitrobenzyl and N-allyl
substituents resulted in enhanced potency, the rest of the
SAR in this series was completed retaining these sub-
units as shown below in Table 2. The sulfone 10h with a
geminal methyl at C-1 showed loss of potency in com-
parison to either 10a or 10f. Interestingly, the alkyl
sulfone analogs 10i–l were all equipotent to 10a. The
replacement of the sulfone moiety by ketone leading to
10m resulted in moderate loss of potency.
As is evident from Table 1, replacement of the C-1
methyl group (10a) by the ethyl analog (10b), resulted in
a 10-fold loss in the binding activity. The analog 10c,
It was our intention to find the most active diastereomer
and evaluate it in the viral infectivity assay and also
subsequently for pharmacokinetic properties. To this
end, we anticipated that the preparation of homochiral
O-nitrobenzyl/N-allyl analogs (10g) might access even
more potent analogs.
Table 1. CCR5 binding activity of sulfonesa
R1
3
O
N
1
SO2Ph
R2
O
N
R3
R4
The binding and antiviral activities for these individual
isomers are displayed in Table 3. As the table reveals,
isomer 16 (1R,3R), and its mirror image analog 19
(1S,3S) were equipotent and at least 3–5-fold better than
17 and 20 in the binding assay. The sulfones 16, 17, 19,
and 20 were also evaluated for their antiviral properties
and the data are shown below.16;17 One notices that the
results from the binding assay for 16, 17, 19, and 20
stand in contrast to the data for the antiviral assay. The
sulfone 16 was 3-fold more potent than 19. Interestingly
both 17 and 19 have very similar antiviral activity. More
surprisingly 20 was 10-fold less active in Hela than 17,
despite having very similar binding potency.
Entry
R1
R2
R3
R4
IC50 (nM)b
10a
10b
10c
10d
10e
10f
10g
Me
Et
H
H
Et
Et
H
8.6
88
H
Me
H
Me
Me
H
Et
Et
H
6.8
24
H
Et
Allyl
Allyl
Allyl
NO2
NO2
NO2
7.2
3.8
4.4
Me
H
Me
Me
a The examples shown are diastereomeric mixtures and prepared
according to Scheme 1.
b The IC50 results are an average of three independent titrations having
calculated standard error below 15% and the variability was generally
3-fold.

3592
K. Shankaran et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3589–3593
Table 3. CCR5 binding/antiviral activity of chiral sulfonesa
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Me
5
N
SO2Ph
O
1
3
N
O
O2N
Entry
Configuration
IC50 (nM)b
Hela IC90 (nM)b
16
17
19
20
1R,3R
1S,3R
1S,3S
1R,3S
2.3
8.4
111
300
3.5
10.4
300
3000
a The examples shown are diastereomeric mixtures and prepared
according to Scheme 1.
b The IC50 results are an average of three independent titrations having
calculated standard error below 15% and the variability was generally
3-fold.
4. (a) Samson, M.; Libert, F.; Doranz, B. J.; Rucker, J.;
Liesnard, C.; Farber, C. M.; Saragosti, S.; Lapoumeroulie,
C.; Cognaux, J.; Forceille, C.; Muyldermans, G.; Ver-
hofstede, C.; Burtonboy, G.; Georges, M.; Imai, T.; Rana,
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Liu, R.; Paxton, W. A.; Choe, S.; Ceradini, D.; Martin, S.
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6. For a comprehensive review on this subject see: Kazmier-
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Watson, C.; Kenaki, T. Bioorg. Med. Chem. 2003, 13,
2663.
Other select racemic sulfone analogs 10e and 10g that
showed potent affinities were screened in the antiviral
assay and the outcome (shown below) was substantially
similar to 17 or 19.
R2
N
SO2Ph
O
R1
O
N
O2N
(+/-)
10e, R1 = H, R2 = Et, IC90 = >1000 nM
10g, R1 = Me, R2 = H, IC90 = 300 nM
7. (a) Dorn, C. P.; Finke, P. E.; Oates, B.; Budhu, R. J.;
Mills, S. G.; MacCos, M.; Malkowitz, L.; Springer, M. S.;
Daugherty, B. L.; Gould, S. L.; DeMartino, J. A.;
Siciliano, S. J.; Carella, A.; Carver, G.; Holmes, K.;
Danzeisen, R.; Hazuda, D.; Kessler, J.; Lineberger, J.;
Miller, M.; Schleif, W. A.; Emini, E. A. Bioorg. Med.
Chem. Lett. 2001, 11, 259; (b) Finke, P. E.; Meurer, L. C.;
Oates, B.; Mills, S. G.; MacCoss, M.; Malkowitz, L.;
Springer, M. S.; Daugherty, B. L.; Gould, S. L.; DeMar-
tino, J. A.; Siciliano, S. J.; Carella, A.; Carver, G.;
Holmes, K.; Danzeisen, R.; Hazuda, D.; Kessler, J.;
Lineberger, J.; Miller, M.; Schleif, W. A.; Emini, E. A.
Bioorg. Med. Chem. Lett. 2001, 11, 255; (c) Finke, P. E.;
Meurer, L. C.; Oates, B.; Shah, S. K.; Loebach, J. L.;
Mills, S. G.; MacCoss, M.; Malkowitz, L.; Springer, M.
S.; Gould, S. L.; Demartino, J. A. Bioorg. Med. Chem.
Lett. 2001, 11, 2469; (d) Finke, P. E.; Meurer, L. C.; Oates,
B.; Mills, S. G.; MacCoss, M.; Malkowitz, L.; Springer,
M. S.; Gould, S. L.; DeMartino, J. A.; Carella, A.; Carver,
G.; Holmes, K.; Danzeisen, R.; Hazuda, D.; Kessler, J.;
Lineberger, J.; Miller, M.; Schleif, W. A.; Emini, E. A.
Bioorg. Med. Chem. Lett. 2001, 11, 2475; (e) Kim, D.;
Wang, L.; Caldwell, C. G.; Chen, P.; Finke, P. E.; Oates,
B.; Mills, S. G.; MacCoss, M.; Malkowitz, L.; Springer,
M. S.; Gould, S. L.; DeMartino, J. A.; Carella, A.; Carver,
G.; Holmes, K.; Danzeisen, R.; Hazuda, D.; Kessler, J.;
Lineberger, J.; Miller, M.; Schleif, W. A.; Emini, E. A.
Bioorg. Med. Chem. Lett. 2001, 11, 3099; (f) Kim, D.;
Wang, L.; Caldwell, C. G.; Chen, P.; Finke, P. E.; Oates,
B.; Mills, S. G.; MacCoss, M.; Malkowitz, L.; Springer,
M. S.; Gould, S. L.; DeMartino, J. A.; Carella, A.; Carver,
G.; Holmes, K.; Danzeisen, R.; Hazuda, D.; Kessler, J.;
Lineberger, J.; Miller, M.; Schleif, W. A.; Emini, E. A.
Bioorg. Med. Chem. Lett. 2001, 11, 3103; (g) Hale, J. J.;
The results shown in Table 3, taken with results for
other analogs, suggest that the potent receptor affinities
for these analogs were not manifested as activity in the
antiviral assay. In general, the sulfones and the N-me-
thyl sulfonamides have similar binding potency, the
difference being that the sulfones are less potent in the
antiviral assay. The sulfone analog 16 was further
evaluated in a rat pharmacokinetic assay. Disappoint-
ingly, it had a moderately high rate of clearance
(Clp ¼ 40 mL/min/kg) and poor oral bioavailability
(9%). For these reasons, additional efforts in pursuit of
sulfone based CCR5 antagonists were curtailed.
In conclusion, a stereospecific synthesis of novel sulf-
ones was developed and analogs thus produced were
assessed for their CCR5 activity. Many of these com-
pounds demonstrated potent binding affinity and mod-
est antiviral properties. Among them the sulfone 16 had
the best profile. It was, however, less active than the
corresponding sulfonamide.
References and notes
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desired product.
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was carried out by mixing 200 lL of 50 nM Hepes buffer,
pH 7.4 containing 5 mM MgCl2, 1 mM CaCl2, 0.5% BSA,
10 lg/mL each of the protease inhibitors aprotinin, chy-
mostatin, and leupeptin, 0.1 mM PMSF, and 0.01 mM
phosphoramidon with 5 lL of compound at increasing
concentration or the DMSO for the background, 20 lL of
125I-MIP-1a (2 · 104 cpm, 2000 Ci/mmol) and 10 lL of
buffer or unlabeled MIP-1a (100 nM final concentration).
Assays were initiated by adding CHO cells (3 · 104) stably
expressing 106 CCR5 receptors/cell and incubated for 1 h
at 24 ꢁC. Separation of free from bound 125I-MIP-1a was
carried out on a Packard Filtermate 196 using GF/C filters
pre-soaked in 0.33% PEI. IC50 values were calculated
using standard methods from the binding results using
final concentrations of test compound in the range from
0.13 to 10,000 nM.
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