[2-(4-Phenyl-4-piperidinyl)ethyl]amine based CCR5 antagonists: derivatizations at the N-terminal of the piperidine ring

Article abstract of DOI:10.1016/j.bmcl.2009.02.014

Several series of CCR5 antagonists have been discovered by derivatization at the N-terminal of the piperidine ring of the core template 2. Some derivatives exhibited potent inhibition against HIV-1infection. The pharmacokinetic properties of the lead comp

Full text of DOI:10.1016/j.bmcl.2009.02.014

Bioorganic & Medicinal Chemistry Letters 19 (2009) 1610–1613
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Bioorganic & Medicinal Chemistry Letters
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[2-(4-Phenyl-4-piperidinyl)ethyl]amine based CCR5 antagonists:
derivatizations at the N-terminal of the piperidine ring
b
a
a
c
Maosheng Duan a, , Christopher Aquino , Robert Ferris , Wieslaw M. Kazmierski , Terry Kenakin ,
*
Cecilia Koble a, Pat Wheelan a, Chris Watson c, Michael Youngman a
a Infectious Diseases Center for Excellence in Drug Discovery, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709, United States
b Metabolic Pathways Center for Excellence in Drug Discover, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709, United States
c Molecular Discovery Research, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Several series of CCR5 antagonists have been discovered by derivatization at the N-terminal of the piper-
idine ring of the core template 2. Some derivatives exhibited potent inhibition against HIV-1infection.
The pharmacokinetic properties of the lead compounds 11a, 14a, 15b, and 16b have been evaluated
in vivo.
Received 9 January 2009
Revised 30 January 2009
Accepted 3 February 2009
Available online 10 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
CCR5
Antagonist
Derivatization
Antiviral
Discovery of the Chemokine Receptor R5 (CCR5) as a co-recep-
tor for HIV-1 infection revealed a novel approach to HIV-1 epi-
demic prevention and treatment.1 CCR5, a member of the 7TM
G-protein coupled receptor (GPCR) family, thus, became an attrac-
tive target pursued by the pharmaceutical industry. Significant re-
search and development efforts have led to several small molecule
clinic candidates2 and one FDA approved drug.3 CCR5 antagonists,
a new class of viral entry inhibitors, offer great promise to be the
next generation of anti-HIV medicines.
4 started from commercially available 4-phenyl-4-piperidinecar-
bonitrile hydrochloride (5). Boc protection of the piperdine ring,
followed by Dibal-H reduction, afforded aldehyde 6, thus, setting
the stage for Wittig olefination with Ph3PCH2OMe. The resulting
Z/E enol ether mixture 7 was then stirred with 90% formic acid at
ambient temperature to produce the homologated aldehyde 4. Its
subsequent reductive amination with 3, and the removal of Boc
group made the core template 2 available (see Ref. 4 for m-F analog
of 2).
Our laboratories have previously reported the identification of a
class of 4,4-disubstituted piperidine carboxamide CCR5 antago-
nists exemplified by 1, demonstrating anti HIV-1 activity (Fig. 1).4
In order to further explore the structure–activity relationship (SAR)
of this class, we then derivatized the core template 2 at the N-ter-
minal of its piperidine ring with a variety of functionalities, leading
to the discovery of several potent series of CCR5 antagonists. Here-
in, we wish to report the syntheses and structure-activity relation-
ship of these series.
Synthesis of 2 was initiated by preparations of 1-(8-azabicy-
clo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole (3) and Boc pro-
tected 4-(2-oxoethyl)-4-phenyl-1-piperidine (4) as depicted in
Scheme 1. Following the literature procedures,4 3 was conve-
niently obtained from readily accessible materials. Preparation of
Derivatization of 2 started with nucleophilic displacements
(Scheme 2). Thus, the treatment of 2 with 2-bromopyrimidine
and N,N-diisopropylethylamine at elevated temperature gave 8a.
Tetrazole 8b was synthesized via a two-step sequence. After instal-
lation of the cyano group to the nitrogen of the piperidine, efficient
5
Bu2SnO-catalyzed cyclization of the resulting nitrile with TMSN3
O
HN
R
N
N
N
H
H
H (F)
N
N
H
H(F)
N
N
H
1
2
* Corresponding author. Fax: +1 919 483 6053.
E-mail addresses: maosheng.a.duan@gsk.com, duanmaosheng@hotmail.com (M.
Duan).
Figure 1. The carboxamide analog and the core template.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.02.014

M. Duan et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1610–1613
1611
Boc
Boc
N,N-diisopropyl amine derivative 9g, the reaction sequence was re-
versed (Scheme 3).
N
HN
N
c
N
N
a,b
O
Reaction of 2 with diphenylcycanocarbonimide under mild con-
ditions afforded piperidinecarboximidoate 10, which served as a
precursor toward two different classes of compounds. Thus, in
RONa/ROH (or RSNa/RSH) medium, displacement of the remaining
phenoxy in 10 readily occurred to yield compounds 11a–c and
12a–c, respectively. Meanwhile, stirring 10 with amines produced
N-cyano-N0-alkyl-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-
azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenyl-1-piperidine carboximi-
damides 13a–b (Scheme 4).
HCl
6
5
7
HN
Boc
N
H
N
d
e, f
3
H
O
N
N
H
Amino acids 14a–g were obtained by a three-component cou-
pling from 2, glycoxylic acid and aryl boronic acids under Petasis
conditions.6 Resulting amino acids were converted either into es-
ters 15a–c or amides 16a–c by standard methods (Scheme 5).
All synthesized compounds were tested for both their ability to
displace [125I]-labeled MIP-1b from the CCR5 receptor expressed
on CHO cell membrane7 and their antiviral activity in HOS cell
against the Ba-L strain of HIV-1.8 The data are presented in Tables
1–5.
Installation of pyrimidine (8a) or tetrazole (8b) to the N-termi-
nal of the piperidine ring in 2 decreased activities by ꢀ10-fold as
compared to the reported carboxamides,4 while the analogues ob-
tained via reductive amination (8c–e) showed improved binding
potencies. Notably, 8e had an IC50 = 3.0 nM in the MIP-1b binding
3HCl
2
4
H
N
H
3
=
N
N
H
Scheme 1. Reagents and conditions: (a) Boc2O, iPr2NEt, CH2Cl2, rt, overnight, 99%;
(b) i-Bu2AlH, CH2Cl2, 0 °C, 1 h, then methanol, citric acid, 88%; (c) Ph3P+CH2OCH3Clꢁ,
NaHMDS, THF, ꢁ78 °C to 0 °C, 68%; (d) 90% formic acid, rt, 2 h, 99%; (e) 3,
NaBH(OAc)3, CH2Cl2, rt, 3.5 h, 82%; (f) HCl, CH2Cl2, rt, 1 h, 99%.
led to 8b. Methylene insertion analogues 8c–e were secured by
reductive amination of 2 with corresponding aldehydes (Scheme
2).
Syntheses of trisubstituted ureas were straightforward (Scheme
3). Commercially available isocyanates were reacted with 2 to give
9a–d. N,N,N0,N0-tetrasubstituted ureas were obtained in a one-pot,
two-step syntheses using phosgene. The in situ generated 4-{2-[3-
(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]eth-
yl}-4-phenyl-1-piperidinecarbonyl chloride was treated with
secondary amines, delivering compounds 9e–f. For the bulky
NC
O
NC
X
N
N
R
N
N
N
b or c or d
N
a
H
H
2
N
N
N
N
H
H
11a-c
12a-c
X=O
X=S
10
13a-b
X=N/NH
R
R'
N
N
Scheme 4. Reagents and conditions: (a) diphenylcyanocarbonimide, Et3N, CH2Cl2,
rt, 4 h, 94%; (b) ROH/NaOR, rt, 1 h, 71–91%; (c) RSH/NaSR, rt, 1 h, 68–99%; (d) amine,
MeOH, rt, overnight, 26–91%.
N
N
H
H
a
e
2
or b,c
N
N
N
N
H
H
R'X
R
O
N
HO
R
O
N
R'=
R=
N
N
8c
8a
8b
N
N
N
N
b or c
N
H
a
H
H
2
N
N
8d
8e
N
Y
Y
N
O
N
N
N
N
H
H
H
15a-c
16a-c
X=O, Y=H
14a-g
X=NH, Y=F
O
Scheme 2. Reagents and conditions: (a) 2-bromopyrimidine, iPr2NEt, DMF, 80 °C,
2.5 h, 65%; (b) BrCN, K2CO3, CHCl3, 61 °C, 4 h, 99%; (c) TMSN3, Bu2SnO, toluene,
90 °C, 6 h, 75%; (e) R0CHO, NaBH(OAc)3, iPr2NEt, CH2Cl2, rt, 3–4 h, 39–87%.
Scheme 5. Reagents and conditions: (a) glyoxylic acid monohydrate, RB(OH)2, Et3N,
THF, rt to 50 °C, 4 h to 2 d, 71–94%; (b) TMSCHN2, MeOH, rt, 1 h, 81–96%, (c) amine,
HATU, Et3N, DMF, rt, 2 h, 33–85%.
O
O
R
R'
N
N
N
N
H
R'
N
N
H
a
H
c, d
2
N
N
N
N
H
H
9e-g
9a-d
Scheme 3. Reagents and conditions: (a) RNCO, CH2Cl2, rt, overnight, 63–99%; (c) phosgene, iPr2NEt, CH2Cl2, rt, 4 h; (d) R02NH, rt, overnight, 57–63%.

1612
M. Duan et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1610–1613
Table 1
Table 4
Inhibitory potency of heterocycle analogues 8a–d in the 125I-[MIP-1b] binding assay
Inhibitory potency of amino acid analogues 14a–g in the 125I-[MIP-1b] binding assay
and HOS cell assay (Scheme 2)
and HOS cell assay (Scheme 5)
Compds
R
R0
MIP-1b IC50
(
lM)
HOS IC50
1.91
(
lM)
Compds
R
Y
MIP-1bC50
(l
M)
HOS IC50
0.0097
(lM)
N
N
14a
H
0.0080
8a
0.32
N
14b
14c
14d
H
F
0.0070
0.0040
0.0070
0.0248
0.0220
0.0292
MeO
F
N
8b
8c
8d
8e
0.129
0.074
0.013
0.003
2.86
N
N
H
N
1.79
N
O
O
H
H
N
0.059
0.035
O
O
14e
H
0.0050
0.0150
14f
H
H
0.0030
0.0230
0.0068
0.0060
Table 2
Inhibitory potency of urea analogues 9a–g in the 125I-[MIP-1b] binding assay and HOS
cell assay (Scheme 3)
S
Cl
14g
Compds
R
R0
MIP-1b IC5O
(
lM)
HOS IC50
0.0420
(lM)
9a
0.0040
Table 5
9b
9c
9d
0.0070
0.0060
0.2650
0.0270
0.1030
2.5690
Inhibitory potency of amino acid derivatives 15a–c and 16a–c in the 125I-[MIP-1b]
binding assay and HOS cell assaya (Scheme 5)
Compds
R
R0
MIP-lb IC50
(lM)
HOS IC50
0.0103
(lM)
15a
CH3
0.0050
F3C
15b
15c
16a
16b
16c
CH3
CH3
H
0.0009
0.0130
n.t.
0.0150
0.2160
0.0520
0.0202
0.7879
F
9e
9f
CH3
0.0210
0.0240
0.1220
0.2400
CH3CH2
9g
0.0180
0.1370
F
F
F
CH3
n-Bu
n.t.
Table 3
Inhibitory potency of cyano-imido(thio)carbamates (11a–c and 12a–c) and guani-
dines 13a–b in the 125I-[MIP-1b] binding assay and HOS cell assaya (Scheme 4)
n.t.
Compds
R
X
O
MIP-1bIC50
(l
M)
HOS IC50
0.0075
(lM)
11a
CH3
0.0020
assay. This suggests that a direct attachment with rings may affect
the conformation of the central piperidine for bindings. More flex-
ible appendage may favor such interactions, which translate into
improved antiviral activity (Table 1).
Trisubstituted ureas (9a–c) improved binding affinities dramat-
ically, reaching single-digit nM levels. Surprisingly, 9d, from the
same group of the urea, had a binding IC50 265 nM. The ꢀ40-fold
decrease in potency was presumably due to the replacement of ali-
phatic moiety with a highly hydrophobic para-trifluoromethyphe-
11b
11c
12a
12b
12c
13a
O
O
S
0.0030
0.0070
0.0230
0.0130
0.0400
0.0110
0.0050
0.0255
0.0371
n.t.
CH3
S
0.1014
0.0.094
0.1086
0.0207
S
Table 6
Pharmacokinetics of the selected compounds 11a, 14a, 15b, and 16b in rat at 1 mg/kg
CH3
NH
N
Compds
Cl (mL/min/kg)
t1/2 (h)
Vdss (L/kg)
%F
11a
14a
15b
16b
22.8
117
39.3
43
2.1
1
15
0
53
37
13b
3.5
6.5
16.5
O
2.3
6.1
a
n.t.: not tested.

M. Duan et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1610–1613
1613
nyl group. Despite their exceptional binding potency, the antiviral
activity of the trisubstituted ureas need to be further enhanced.
Meanwhile, the tetrasubstituted ureas (9e–f) were less impressive
due to their relatively lower IC50s in both the binding and antiviral
assays (Table 2).
clearance, but its bioavailability was moderate (15%). Disappoint-
ingly, 14a, a representative of the most potent series had no oral
exposure due to extremely high clearance and potentially poor
permeability. Masking carboxylic acid functionality of 14c either
as an ester 15b or as an amide 16b did boost bioavailability, but
their clearances remained high (Table 6).
In conclusion, several series of potent CCR5 antagonists have
been discovered via derivatization at the N-terminal of the piperi-
dine ring of 2. All compounds were tested for both binding and
antiviral activities. Amino acid derivatives have shown significant
promise, but their PK properties need further improvement.
Cyano-imidocarbamates (11a–c) demonstrated comparable
binding affinity to the trisubstituted ureas. Moreover, 11a turned
out to be highly potent in antiviral inhibition with HOS
IC50 = 7.5 nM. Their thio counterparts (12a–c) and the cyano-gua-
nidine analogues (13a–b) were, however, less active (Table 3).
Amino acids (14a–g) were a very promising series, which, in
general, retained the binding potency in the single-digit nM range.
Importantly, their potent binding affinities successfully translated
into high antiviral activities as shown in Table 4 (14a, 14f, and
14g). In addition, it was observed that amino acid analogues helped
to minimize hERG/QTc liabilities sometimes observed with related
series discussed elsewhere (Kazmierski, Duan et al. manuscript in
preparation) presumably due to the polarities of the amino acids.
Conversion of selected amino acid analogues into esters (15a–c)
or amides (16a–c) with the aim of improving cell permeability ap-
peared to have no significant impact on the activity, except that
relatively large amine was incorporated (16c) (Table 5).
References and notes
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Cayanan, C.; Maddaon, J. P.; Koup, A. R.; Morroe, P. J., et al Nature 1996, 381, 667.
2. Kazmierski, W. M.; Gudmundsson, K. S.; Piscitelli, S. C. Annu. Rep. Med. Chem.
2007, 42, 301.
3. Wood, A.; Armour, D. Prog. Med. Chem. 2005, 43, 239.
4. Kazmierski, W. M.; Aquino, C.; Chauder, B.; Deanda, F.; Ferris, R.; Jones-Hertog,
D.; Kenakin, T.; Koble, C.; Watson, C.; Wheelan, P.; Yang, H.; Youngman, M. J.
Med. Chem. 2008, 51, 6538.
5. Wittenberger, S. J.; Donner, B. G. J. Org. Chem. 1993, 58, 4139.
6. Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445.
7. Watson, C.; Jenkinson, S.; Kazierski, W.; Kenakin, T. Mol. Pharmacol. 2005, 67,
1268.
8. Jenkinson, S.; McCoy, D.; Kener, S.; Ferris, R.; Lawrence, W.; Fox, T.; Smith, C.
Recept. Channels 2003, 9, 117.
The pharmacokinetics of lead compounds 11a, 14a, 15b, and
16b were evaluated in Sprague Dawley rats at 1 mg/kg using 5%
mannitol with 0.05% acetic acid as dose vehicle. 11a had acceptable