1-Amido-1-phenyl-3-piperidinylbutanes - CCR5 antagonists for the treatment of HIV. Part 1

Article abstract of DOI:10.1016/j.bmcl.2009.01.009

The development of a new class of CCR5 antagonist replacing the tropane core of maraviroc by piperidine with a branched N-substituent is described. Compound 15h shows good whole cell antiviral activity together with microsomal stability and only weak activity at the hERG ion channel.

Full text of DOI:10.1016/j.bmcl.2009.01.009

Bioorganic & Medicinal Chemistry Letters 19 (2009) 1075–1079
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
1-Amido-1-phenyl-3-piperidinylbutanes — CCR5 antagonists for the treatment
of HIV. Part 1
*
Christopher G. Barber , David C. Blakemore, Jean-Yves Chiva, Rachel L. Eastwood,
Donald S. Middleton, Kerry A. Paradowski
Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The development of a new class of CCR5 antagonist replacing the tropane core of maraviroc by piperidine
with a branched N-substituent is described. Compound 15h shows good whole cell antiviral activity
together with microsomal stability and only weak activity at the hERG ion channel.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 12 December 2008
Revised 5 January 2009
Accepted 6 January 2009
Available online 10 January 2009
Keywords:
HIV
CCR5
Antiviral
Antagonist
The retrovirus HIV (human immunodeficiency virus) can lead to
acquired immunodeficiency syndrome (AIDS), a potentially fatal
condition resulting from the failure of the immune system. Since
its recognition as a disease in 1981,1 efforts to identify treatments
have been frustrated by the rapidity with which mutations which
confer resistance can arise, leading to the drive to identify alterna-
tive points of intervention in the viral cycle. Maraviroc is the first of
a number of CCR5 antagonists that have been developed to block
viral entry into cells and was approved by the FDA for the treat-
ment of HIV in 2007.2,3
Following the discovery of maraviroc and related tropane-based
CCR5 antagonists,4 we wished to identify a novel chemotype that
could capitalise upon different interactions and thereby potentially
offer us a different resistance profile.5 We were particularly inter-
ested in replacing the central tropane core since this had been a
common feature of all our previous candidates. However, our expe-
rience suggested this would be a significant challenge since the
tropane offered several key advantages. It had initially been
designed to reduce the ability of the central N atom to bind to
Asp301 of CYP2D6—activity against this could bring unwanted
drug–drug interactions.6 However, the tropane bridge had also
often given a potency increase in our cell-based gp160 fusion
assay, and at times, had also proven beneficial for antiviral activ-
ity.7 For example, antiviral activity was lost when this bridge was
removed from maraviroc (1) to give 2 (Table 1). While the mecha-
nisms for increased fusion potency or for the disproportionate
increase in antiviral activity resulting from the incorporation of
the tropane bridge are unknown, it is clear that such a modification
increases steric hindrance around the central basic centre and
restricts the conformational flexibility of the molecule. We pro-
posed that similar steric and conformational effects could also be
achieved through the addition of an alpha methyl branch onto
the 3-amino-3-phenyl-propyl side chain (Fig. 1). Initially we pre-
pared a series of 4-amido-piperidines as these were readily acces-
sible and previous SAR had demonstrated that these would provide
a reasonable level of potency. For example, 3, a tropane with a sim-
ple phenylacetic amide substituent, showed good potency in our
cell fusion assay. Removal of the tropane bridge and the ethyl sub-
stituent gave 4 which showed a loss of fourfold in potency but still
retained some antiviral activity. However, the a-methyl derivative
5 showed a two- to threefold increase in potency in our gp160
fusion assay over the equivalent tropane (3) supporting further
exploration of this novel core.
Our initial synthesis did not offer any stereochemical control at
the newly formed centre in the reductive amination step and com-
pounds were tested as an approximately 1:1 mixture of diastereo-
mers (Scheme 1). The b-amino ester 6 was converted to the
cyclobutyl amide by treatment with cyclobutyl carboxylic acid
chloride. Direct conversion of the ester to Weinreb amide 88 was
followed by reaction with methyl magnesium bromide to afford
methyl ketone 9.
The central fragment was prepared from 10 by reductive amina-
tion with ethylamine followed by N-Boc protection to give 12. This
* Corresponding author. Tel.: +44 1304 641182.
E-mail address: christopher.barber@pfizer.com (C.G. Barber).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.01.009

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C. G. Barber et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1075–1079
Table 1
Cell fusion and antiviral activities for maraviroc and related analogues
a
b
d
Compound
Structure
Fusion IC50
0.2 nM
AV IC90
logD7.4
pKa
HLM Clc
hERG inhibition
0% @ 300 nM
O
F
F
N
1
0.7 nM
2.0
7.7
22
N
N
N
N
N
O
F
F
N
29
7.5 nM
Inactive
1.7
2.9
7.2
8.7
<8
0% @ 300 nM
N
N
N
O
N
3
14 nM
—
183
IC50 = 248 nM
N
O
O
N
O
O
N
N
410
48 nM
310 nM
2.2
8.2
7.8
—
Not tested
O
N
N
O
N
N
O
5
5 nM
—
—
137
Not tested
O
a
Cell fusion assay.7
b
c
Antiviral activity—concentration required to inhibit replication of HIVBal in PM-1 cells by 90%.
Human liver microsome stability ( l/min/mg of microsomal protein).
The concentration required to inhibit [3H]dofetilide binding to hERG stably expressed on HEK-293 cells.
l
d
was reductively coupled to ketone 9 in the presence of Ti(OiPr)4
providing 13 as a mixture of isomers. Deprotection and acylation
gave analogues 14 as an approximate 1:1 mixture of isomers.
A series of analogues were prepared (Table 2). Changes in the
aryl substituent of phenyl acetic acid moiety (examples 14a–14j)
gave a 3-log unit spread in activity in our cell fusion assay. While
substitution at the 2-position was less favoured, potency increased
with lipophilicity in the 3 or 4-position and also with electron
withdrawing substituents in the 4-position. A similar trend was
observed in a related series by Burrows.11 In particular 3,4-diCl
(14a) and 4-CF3 (14c) showed particularly high potencies that
translated into excellent levels of activity in our whole cell antivi-
ral assay with IC90’s of 0.20 and 0.24 nM, respectively. Substitution
at the benzylic carbon (14k) was not tolerated, however the amide
could be replaced with a urea, and to a lesser extent with a carba-
mate. Urea 14l showed pM activity in our cell fusion assay, but this
10-fold increase over the activity seen with 14a did not translate
into higher efficacy in the antiviral assay. Such a non-linear rela-
tionship between cell fusion-based assays and whole cell antiviral
assays has previously been reported.12 Additional substitution to
give a tetrasubstituted urea was not tolerated (14n). Benzyl or phe-
nyl carbamates 14o and 14q showed equivalent potency in the cell
fusion assay, although again the antiviral activities were signifi-
cantly different with only 14o showing good activity.
While good levels of antiviral activity were observed, we felt
that this series was flawed. With the notable exception of sul-
phone 14e, we appeared to be locked into relatively lipophilic
series with significant metabolic vulnerability. Even 14e with a
modest logD7.4 of 1.8 was rapidly turned over in HLM
(Cl = 379 ll/min/mg microsomal protein) which we propose is
as a result of N-de-ethylation since the dealkylated derivative
showed considerably better microsomal stability (data not
shown). While potency was not significantly reduced when the
N-ethyl group was removed, previous experience had suggested
that the removal of the ethyl group would expose a second
Figure 1. Low energy conformations of 1 and 5.

C. G. Barber et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1075–1079
1077
O
NH2
O
NH
O
7
8
9
R1 = OEt
N(OMe)Me
Me
i
ii
R1
iii
O
6
v
iv
Bn
N
N
H
Bn
N
O
HN
N
vi
Boc
10
11
12
O
O
NH
NH
R2
N
O
vii, viii
N
Boc
N
X
N
14
13
Scheme 1. Preparation of 1-amido-1-phenyl-3-piperidinylbutanes. Reagents and conditions: i—cBuCOCl, Et3N, CH2Cl2, 0 °C, 98%; ii—MeNHOMe.HCl, iPrMgCl, THF, <4 °C, 77%;
iii—MeMgBr, THF, À68 °C, 74%; iv—(a) EtNH2, THF; (b) Na(OAc)3BH, RT, 100%; v—(a) Boc2O, CH2Cl2, RT, 100%; (b) 10% Pd/C, H2 50 psi, 50 °C, EtOH, 97%; vi—9, Ti(OiPr)4,
NaBH3CN, CH2Cl2, MeOH, 67%; vii—HCl, Et2O; viii—X = CH2 or CMe2: phenylacetic acid, CDI, Et3N, CH2Cl2, 87–100%; X = NCH2: ArNCO, CH2Cl2, 59–95%; X = NHMe: (a)
PhNHMe, triphosgene, Et3N, CH2Cl2; (b) Et3N, THF, 13, reflux, 78%; X = OCH2 or O: carbamoyl chloride, Et3N, CH2Cl2, RT, 51–84%; X = bond: benzoic acid, HOBT, Et3N, CH2Cl2,
45–65%.
H-bond acceptor which would limit the potential for oral
absorption. An analysis of 215 project compounds with similar
molecular weights and numbers of H-bond acceptors and for
which caco-2 flux had been measured, showed the probability
of good caco-2 flux decreased significantly with increasing num-
ber of H-bond donors (Table 3). With 2 or more H-bond donors,
the probability of a level of caco-2 flux predictive for good oral
absorption was reduced to 10%. Removal of the amidic proton
on the propyl side chain was not tolerated. For example N-meth-
ylation of 1 resulted in a >1000-fold fall-of in activity. Conse-
Table 3
Percentage of compounds with caco-2 flux (apical–basal) Papp >2 Â 10À6 cm/s
(supportive of good oral absorption13
)
No. of H-bond donors
0
1
> 2
clogP > 2.5
clogP < 2.5
86%, n = 35
33%, n = 49
35%, n = 60
7%, n = 61
20%, n = 5
0%, n = 5
quently we wished to identify alternative structures that would
avoid N-dealkylation but not introduce a second H-bond donor
(see Table 4).
Table 2
Heterocycles have been investigated as bioisosteres of amides
and with some success against the CCR5 receptor.14
Activity of 1-amido-1-phenyl-3-piperidinylbutanes
O
The 4-heterocycle substituted piperidines 15 were prepared by
reductive amination of imines formed via Ti(OiPr)4-mediated dehy-
dration of ketone 9 and the appropriate piperidine as shown in
Scheme 2.
NH
N
O
While our first example, 15a, a cyclic analogue of the open-
chained urea 14i showed little activity, further examples without
the additional phenyl ring were more encouraging. Pyrazole 15b
showed modest levels of activity with improved metabolic stabil-
ity. The 1,3,4-oxadiazoles 15c and 15d retained some cell fusion
activity, exhibited no observable turnover in human liver micro-
somes and also benefited from a significant drop in hERG activity.
The latter gave us confidence that we would be able to design out
this unwanted activity. Isomeric 1,2,4-oxadiazole 15e although
more potent than 15d was significantly more lipophilic and rein-
troduced metabolic vulnerability. Switching to the 1,3,4-triazoles
15g and 15h gave us potency, metabolic stability and, in the case
of 15h, only weak activity against the hERG ion channel.
Since these 4-heterocyclic piperidines were still un-resolved at
N
X
R
Compound
R
X
Fusion IC50, nM
clogP
AV IC90, nM
0.20
14a
14b
14c
14d
14e
14f
14g
14h
14i
3,4-diCl
4-Cl
4-CF3
4-F
4-SO2Me
3-Cl
2,4-diCl
4-Me
H
2-OMe
H
3,4-diCl
H
H
H
4-Cl
4-F
4-F
4-Cl
3,4-diCl
4-OMe
H
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CMe2
NHCH2
NHCH2
NMe
OCH2
O
0.05
0.34
0.48
0.94
0.07
1.54
2.33
3.76
13.4
17.9
>25,000
0.003
0.16
6,430
3.16
3.4
5.17
4.58
4.75
4.01
2.22
4.58
5.29
4.36
3.78
3.86
4.57
5.24
3.93
4.16
5.1
5.18
4.61
3.72
4.29
4.91
3.72
3.50
0.24
2.81
14j
14k
14l
0.236
0.322
the a-methyl stereocentre, the diastereomeric isomers of 15h were
14m
14n
14o
14p
14q
14r
14s
14t
14u
14v
separated by column chromatography. As expected, both isomers
showed no measurable turnover in HLM. There was a 15-fold split
in their relative activities in the cell fusion assay (IC50 = 4.3 and
60 nM). The more active isomer showed the higher level of activity
O
—
—
—
—
—
3.63
4.83
25.3
33.7
64.4
73.5
61.4
1630
at the hERG channel (IC50 = 2.1 vs 7.1 lM) but was still sufficiently
weak to give us confidence that this series merited further investi-
gation. This work will be described in a subsequent paper along
with the stereochemical assignment of the more active species.

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C. G. Barber et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1075–1079
Table 4
Activity of key 4-heterocyclic piperidines
O
NH
N
R1
Compounda
R1
Fusion IC50, nM
2310
logD7.4
HLMb
35
hERG IC50, nM
O
N
15a15
N
3.5
4.7
Ph
N
15b
382
2.4
38
117
N
N
N
15c16
15d17
540
1.1
1.3
<7
<7
3100
O
N
N
O
1849
<5280
N
N
N
15e18
15f19
21.4
94.6
2.1
3.2
56
Not tested
1650
N
O
N
204
N
N
O
15g9
37.5
2.0
1.2
1.9
<7
<7
849
N
N
N
15h9
4000
N
N
a
Precursor 4-heterocyclepiperidine.
b
(ll/min/mg of microsomal protein).
O
O
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NH
i
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O
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9
15
R
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We have developed a replacement to the tropane core which is
a key feature to the profile exhibited by maraviroc. Sterically
encumbering the central nitrogen with an a-methyl group gave a
series with good whole cell antiviral activity, metabolic stability
and a significant window over activity at the hERG ion channel.
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