Design and synthesis of pyridin-2-yloxymethylpiperidin-1-ylbutyl amide CCR5 antagonists that are potent inhibitors of M-tropic (R5) HIV-1 replication

Article abstract of DOI:10.1016/j.bmcl.2011.02.058

A novel series of CCR5 antagonists were identified based on the redesign of Schering C. An SAR was established based on inhibition of CCR5 (RANTES) binding and these compounds exhibited potent inhibition of R5 HIV-1 replication in peripheral blood mononuclear cells.

Full text of DOI:10.1016/j.bmcl.2011.02.058

Bioorganic & Medicinal Chemistry Letters 21 (2011) 2450–2455
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and synthesis of pyridin-2-yloxymethylpiperidin-1-ylbutyl amide
CCR5 antagonists that are potent inhibitors of M-tropic (R5) HIV-1 replication
Renato Skerlj a, , Gary Bridger b, Yuanxi Zhou b, Elyse Bourque a, Jonathan Langille b, Maria Di Fluri b,
⇑
David Bogucki b, Wen Yang b, Tongshuang Li b, Letian Wang b, Susan Nan b, Ian Baird b, Markus Metz a,
Marilyn Darkes b, Jean Labrecque b, Gloria Lau a, Simon Fricker a, Dana Huskens c, Dominique Schols c
a Genzyme Corp., 153 Second Avenue, Waltham, MA 02451, USA
b AnorMED, Inc., 200-20353 64th Avenue, Langley, British Columbia, Canada V2Y 1N5
c Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of CCR5 antagonists were identified based on the redesign of Schering C. An SAR was estab-
lished based on inhibition of CCR5 (RANTES) binding and these compounds exhibited potent inhibition of
R5 HIV-1 replication in peripheral blood mononuclear cells.
Received 17 January 2011
Revised 9 February 2011
Accepted 14 February 2011
Available online 23 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
CCR5
Chemokine receptor
HIV-1
Schering C
The discovery of the chemokine receptors CXCR4 and CCR5 in
1996 as co-receptors1 for HIV-1 entry into cells prompted a global
research effort to discover novel antagonists of these receptors. Gi-
ven that individuals harboring the homozygous form of the CCR5
delta 32 allele are highly resistant to macrophage-tropic (M-tro-
pic), CCR5-tropic or R5 HIV-1 infection2 and that the M-tropic
strain is the most prevalent strain the chemokine receptor CCR5
was established as an important and novel target for potentially
preventing HIV-1 infection. As a consequence there was a con-
certed effort by many of the large pharmaceutical companies to
identify and develop a small molecule antagonist of CCR5.3 Ulti-
mately Pfizer was successful at obtaining FDA approval for marav-
iroc in 2007 for treatment experienced patients infected
exclusively with CCR5-tropic HIV-1 virus and following further
clinical trials maraviroc was approved for use in treatment-naïve
patients with CCR5-tropic virus in 2009.4
EtO
EtO
N
N
N
Br
Br
Schering C (1)
N
N+
O-
O
N
Cl
N
H
N
2
O
Cl
OR1
1
3
4
, R = aryl, heteroaryl
Cl
N
H
N
N
1
R
, R = 2-pyridyl
O
Cl
Figure 1. Structure of Schering C (1) and related analogs 2–4.
We have had a longstanding research interest in developing
small molecule antagonists of CXCR4 and have demonstrated that
blocking CXCR4 with small molecule antagonists, AMD31005 and
AMD070,6 results in viral load reduction in T tropic (X4) HIV-1 in-
fected patients.7,8 Given the prevalence of M-tropic strains of HIV-1
we were also interested in developing a small molecule antagonist
of CCR5 which could potentially be used in combination with a
CXCR4 antagonist. In addition, the emergence of T-tropic or X4
HIV-1 variants in a minority of HIV-1 infected persons has been ob-
served following treatment with maraviroc.9 This development
strongly suggests that a combination of CCR5 and CXCR4 antago-
nists for treatment of dual/mixed tropic HIV-1 infection will be re-
quired for complete viral suppression.
Our medicinal chemistry strategy was to modify the lead com-
pound in clinical development at the time, Schering C (1) or SCH
⇑
Corresponding author. Tel.: +1 781 434 3684; fax: +1 781 672 5823.
E-mail address: renato.skerlj@genzyme.com (R. Skerlj).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.02.058

R. Skerlj et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2450–2455
2451
351125.10 The tactic was to redesign 1 by first opening up the low-
er piperidine ring and then find a replacement for the oxime moi-
ety to afford analogs 3 and 4 (Fig. 1). The 125I RANTES competitive
binding assay11 was used to establish a structure activity relation-
ship (SAR) and the anti-HIV-1 activity was assessed utilizing the R5
HIV-1 PBMC assay.12
replacement of the methyl group with the more sterically demand-
ing ethyl 1e resulted in a marked decrease in binding inhibition to
CCR5. In addition, alkylation of the amide nitrogen with a methyl
group 1f rendered the compound inactive, in stark contrast to 1.
A preliminary effort was also expended on finding a replacement
for the amide N-oxide, since in several cases rotamers were ob-
served as was also reported for 1,13 and this resulted in the
identification of the 3,5-dichloropyridine moiety as a suitable
replacement. For example, the binding inhibition of compound 2
containing the 3,5-dichloropyridine moiety was comparable to 1a
and 1d. The importance of the methyl stereocenter was confirmed
by the gem dimethyl 1g and cyclopropyl analogs 1h which were
15-fold and 165-fold less potent in inhibitory binding compared
to 1f. Based on this data we concluded that the optimal replace-
ment of the piperidine ring was the isobutyl chain attached to a
secondary amide with a 3,5-dichloropyridine moiety as exempli-
fied by compound 2.
Modification of the lower piperidine ring was carried out to find
a suitable ring replacement (Table 1) with a direct comparison to 1
which has an IC50 of 0.04
lM in the competitive binding assay and
an IC50 of 0.160 M in the HIV-1 PBMC assay. The compounds in
l
Table 1 were all prepared as the E-isomer at the oxime similar to
1. Simply disconnecting the C–C bond at the quaternary carbon
atom afforded the isobutyl chain derivative 1d that was sevenfold
less potent in binding (IC50 of 0.29
lM) compared to 1 whilst still
retaining antiviral activity but at a reduced level of 2.5
lM. The clo-
sely related propyl analog 1a although comparable in potency to
1d was cytotoxic and therefore not further evaluated. Interestingly
Table 1
CC-Chemokine RANTES binding inhibition, anti-HIV-1 (BaL) activity and cellular cytotoxicity of compound 1 analogs and compound 2a
EtO
N
N
Br
N
N+
O-
O
Linker
b
c
d
Compd
Linker
125I RANTES binding IC50
(lM)
HIV-1 PBMC IC50
(
lM)
PBMC CC50
>1.6
(lM)
1
N
N+
O-
0.04 (n = 9)
0.16 (n = 3)
O
H
N
N+
O-
1a
1b
1c
1d
1e
1f
0.18 (n = 2)
na
>1.5
7.5
195.8
O
H
N
N+
O-
>39.17
>36.41
2.54
O
O
H
N
N+
O-
17.01
0.29
182.1
H
N
N+
O-
>177.9
>177.9
>182.7
O
O
O
H
N
N+
O-
na
>32.76
>36.54
Et
N
N+
O-
5.62
Cl
N
H
N
2
0.13
>6.70
>6.60
>6.81
33.8
33.0
34.0
O
O
O
Cl
Cl
N
H
N
1g
1h
21.37
1.76
Cl
Cl
N
H
N
Cl
a
Assays were performed in duplicate and values represent the mean with standard deviations <30% of the mean. Bracketed values represent
the number of experiments.
b
CCR5 competitive ligand binding assays were performed with 125I-RANTES on membranes prepared from HEK293F cells transfected to
express CCR5.
c
Peripheral blood mononuclear cells (PBMC) were isolated from healthy volunteers and infected by R5 HIV-1 (BaL strain) as reported in Ref.
12. IC50 is the concentration of the compound required to inhibit viral replication by 50% as measured by p-24 HIV-1 specific Ag ELISA.
d
CC50 is the concentration required to reduce the viability of PBMC by 50%.

2452
R. Skerlj et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2450–2455
amination (1c, 1e) or N-alkylation with a Michael acceptor (1a-b,
O
O
O
O
a-c
Br
d, e
1d, 1f, 2) to install the linker moiety. For example, in the synthesis
of compound 2 the isobutyl amine 6a, was prepared by Michael
addition of the amine 5 to but-2-enenitrile followed by reduction
of the nitrile to the primary amine using BH3ÁMe2S and finally
hydrolysis of the ketal to the ketone using aqueous HCl. To com-
plete the synthesis of 2 the amide and (E)-oxime were installed
as reported by Palani et al.10 In contrast, for compounds 1c and
1e the linker was added by reductive amination of 5 with t-butyl
(2-oxopropyl)carbamate14 or t-butyl (3-oxopentyl)carbamate15 in
the presence of NaBH3CN. For compound 1g, the cyclopropyl moi-
ety of 7 was synthesized by cyclopropanation of the corresponding
amide which was obtained by reaction of 5 with 3,3-diethoxyprop-
anoic acid. Functional group manipulation converted the acetal of
7 to the Boc protected amine 8 which was subsequently converted
to 1h after formation of the oxime and amide.
We next turned our attention to finding an appropriate replace-
ment for the oxime moiety of compound 2 (Table 2). Locking the
oxime into a six-membered ring (2a) resulted in a substantial loss
in activity compared to 2. In addition replacing the oxime with a
ketone 2b or hydroxyl group 2c also had a deleterious effect on
activity. However, we were encouraged to find that the O-aryl ana-
log 2d resulted in a comparable binding inhibition to 2, with an
N
NH2
( )n
NH
N
Br
R
5
6, R=H
1a, R=H, n=2
f, g
O
6a
, R=Me
1b
, R=H, n=1
1c, R=Me, n=0
1d, R=Me, n=1
1e
, R=Et, n=1
Br
R1
2, R=Me, n=1
7, R1 = CH(OEt)2
, R = CH2NHBoc
e, n, d
h-m
1
1g
8
Scheme 1. Reagents and conditions: (a) RCH@CHCN, MeOH, 59–66%; or t-butyl (3-
oxopentyl)carbamate, or t-butyl (2-oxopropyl)carbamate, NaBH3CN, MeOH, 60 °C,
20–56%; (b) BH3ÁMe2S, THF; (c) HCl/H2O or 6 N HCl, EtOAc, 40–60% over two steps;
(d) HOBt, EDCI/ArCO2H, 59–89%; (e) EtONH2ÁHCl, MeOH, 32–78%; (f) 3,3-diethoxy-
propanoic acid, EDCI, HOBt, 66%; (g) EtMgBr, Ti(OiPr)4, Et2O/THF, 22%; (h) TFA,
CHCl3, 0 °C; (i) NaBH4, MeOH, 83% over two steps; (j) MsCl, TEA, CH2Cl2; (k) NaN3,
DMF, 67% over two steps; (l) Ph3P, THF, H2O, 76%; (m) Boc2O, THF, 84%; (n) TFA,
CH2Cl2, 100%.
The compounds in Table 1 were synthesized using the advanced
intermediate 510 (Scheme 1) which underwent either reductive
Table 2
CC-Chemokine RANTES binding inhibition, anti-HIV-1 (BaL) activity and cellular cytotoxicity of compound 2 analogsa
EtO
N
Cl
N
H
N
N
Br
O
Cl
R
Compd
R
125I RANTES binding IC50
(l
M)
HIV-1 PBMC IC50
(
lM)
PBMC CC50
185.1
(lM)
O
N
2a
12.25 (n = 2)
>7.4
N
N
N
Br
Br
Br
O
2b
2c
na
32.6
188.6
198.3
OH
3.39
>39.6
O
N
2d
2e
0.13
0.03
>1.3
0.22
31.7
4.28
N
N
Br
Br
O
2f
0.04 (n = 2)
0.22
33.8
7.8
N
F3C
O
O
2g
0.03
0.01 (n = 3)
N
F3C
a
See footnotes in Table 1.

R. Skerlj et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2450–2455
2453
precursor to 2g, was readily prepared by reaction of 11 with cate-
chol in the presence of p-TsOH in refluxing xylene. In contrast, the
spiro benzofuran 2f was prepared from the intermediate 15. Reac-
tion of 11 with the Grignard of 1-bromo-(2-bromomethyl)benzene
afforded the tertiary alcohol 14 which underwent an intramolecu-
lar Pd(0) catalyzed coupling17 with the bromobenzene moiety fol-
lowed by Boc deprotection to afford 15. Reduction of 11 to the
alcohol provided ready access to the O-aryl compounds (Table 3)
which were prepared using Mitsunobu chemistry. The O-pyridyl
compounds (Table 4) were prepared either by O-alkylation of the
corresponding alkoxide or by Mitsunobu chemistry. For example,
reaction of the alkoxide with 2-chloro-6-cyanopyridine gave the
O-pyridyl intermediate which afforded 4p18 using the methodol-
ogy described in Scheme 1.
The SAR that was developed for the O-aryl series is shown in Ta-
ble 3. Although the molecules contain two stereocenters the SAR
was based on the diastereoisomeric mixtures. In an effort to find
a replacement for the bromide it was found that the CF3 group pro-
vided the best overall enhancement in binding inhibition, for
example, the IC50 for RANTES binding inhibition of 3a was
HO
HO
O
OH
N
I
a
b-e
NBoc
Br
NH
2a
Br
Br
9
10
Scheme 2. Reagents and conditions: (a) n-BuLi, THF, N-Boc-4-formylpiperidine,
TMEDA, 50%; (b) N-hydroxy phthalimide, DIAD, PPh3, THF, 60%; (c) PCC, SiO2,
CH2Cl2, 90%; (d) hydrazine, EtOH; (e) TFA, CH2Cl2, 80% over two steps.
IC50 of 0.13 lM and an antiviral activity in the low lM range. Inter-
estingly, the aniline analog 2e resulted in approximately a 10-fold
increase in both binding inhibition and anti-HIV-1 activity com-
pared to 2. A further modification that appeared promising was
the spiro benzopyran analog 2f and the spiro benzoketal 2g both
of which potently inhibited CCR5 ligand (RANTES) binding with
an IC50 of 0.04 lM and 0.03 lM, respectively. More importantly,
the antiviral activity of 2f was comparable to the aniline analog,
whereas the benzoketal 2g was 10-fold more potent with an IC50
of 0.01 lM. However, the spiro benzopyrans were discounted early
on due to synthetic challenges and although the spiro benzoketals
had exceptional pharmacokinetic properties the series was not fur-
ther pursued due to muscarinic receptor cross-reactivity.16 How-
ever, both the O-aryl series and the aniline series were further
advanced and the O-aryl series are the subject of this Letter.
The benzo oximine 2a was prepared from commercially avail-
able 5-bromo-(2-iodophenyl)methanol (Scheme 2) by regioselec-
tive lithiation using n-BuLi followed by reaction with N-Boc-4-
formylpiperidine to afford the diol 9 in 50% yield. The oximine ring
was formed by Mitsunobu reaction of the primary alcohol with N-
hydroxy phthalimide to afford the alkoxy phthalimide. Oxidation
of the secondary alcohol to the ketone followed by treatment with
hydrazine liberated the amine which underwent an intramolecular
cyclization to afford the oximine. Boc cleavage under acidic condi-
tions gave 10 which was then converted to 2a using conditions
from Scheme 1.
The intermediate 11 is illustrative of the methodology used to
prepare many of the compounds in Tables 2–4 (Scheme 3). Com-
pounds containing other substituents in the place of the CF3 group
were synthesized in a similar manner. Compound 11 was simply
prepared by the addition of lithiated 2-bromo-4-(trifluoro-
methyl)benzene to N-Boc-2-formylpiperidine followed by oxida-
tion of the alcohol to the ketone. The benzoketal 12, the
0.05 lM vs 0.13 lM for 2e. Substitution of electron withdrawing
cyano or chloro groups at the 3-position resulted in improved
potencies compared to the 2-substituted analogs. For example,
the 3-cyano analog 3c resulted in a twofold improvement in bind-
ing inhibition (IC50 of 0.05
viral activity (IC50 of 0.48
Similarly, the 3-chloro analog 3e gave a comparable improvement
in binding inhibition (IC50 of 0.06 M) and a 15-fold improvement
in antiviral activity (IC50 of 0.075 M) compared to the 2-chloro
analog 3d. The most potent antiviral analog in this series was the
3-CF3 analog 3g with an antiviral IC50 of 0.03 M, fivefold more po-
lM) and a fivefold improvement in anti-
l
M) compared to the 2-cyano analog 3b.
l
l
l
tent then 1. Interestingly the methyl ester 3j resulted in a dramatic
loss in antiviral activity. Further evidence that electron withdraw-
ing groups provide a benefit in antiviral potency was the fivefold
enhancement gained with the 3-F analog 3i compared to the phe-
nyl group 3a, IC50 of 0.23 lM versus 1.27 lM. Although the po-
tency of this series was promising the lipophilicity as measured
by c Log P exceeded 5 very likely contributing to poor oral absorp-
tion and as a consequence the more hydrophilic pyridyl analogs
3k–m were synthesized. We were pleased to find that the 2-pyri-
dyl analog 3k had acceptable binding and viral inhibitory activity
to warrant further investigation.
Table 3
CC-Chemokine RANTES binding inhibition, anti-HIV-1 (BaL) activity and cellular cytotoxicity of compounds 3a
OR1
Cl
N
H
N
N
R
O
Cl
Compd
R
R1
125I RANTES binding IC50
(lM)
HIV-1 PBMC IC50
(lM)
PBMC CC50 (lM)
3a
3b
3c
3d
3e
3f
3g
3h
3i
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
Br
Ph
0.05
0.10
0.05
0.12
0.06
na
1.27
2.87
0.48
>1.27
0.07
0.10
0.03
>1.23
0.23
>6.26
3.76
3.30
6.8
17.0
15.7
4.4
8.1
12.5
7.0
3.1
5.4
15.2
33.7
32.5
31.2
2-CNPh
3-CNPh
2-ClPh
3-ClPh
2-CF3Ph
3-CF3Ph
4-CF3Ph
3-FPh
3-CO2MePh
2-Pyridyl
3-Pyridyl
4-Pyridyl
na
na
0.04
na
0.14 (n = 4)
0.97
na
3j
3k
3l
Br
Br
3m
>0.24
a
See footnotes in Table 1.

2454
R. Skerlj et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2450–2455
Table 4
CC-Chemokine RANTES binding inhibition, anti-HIV-1 (BaL) activity and cellular cytotoxicity for compounds 4a
4
3
5
R1
6
O
N
Cl
N
H
N
N
R
O
Cl
Compd
R
R1
125I RANTES binding IC50
(l
M)
HIV-1 PBMC IC50
(
lM)
PBMC CC50 (lM)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
Br
Br
Br
Br
3-Me
4-Me
5-Me
6-Me
3-Me
4-Me
6-Me
3-Cl
4-Cl
6-Cl
6-Cl
6-Cl
0.19
0.14
3.80
0.22
0.06
0.05
0.04
0.14
0.07
0.02 (n = 2)
0.03
0.01
0.03
na
0.34
1.96 (n = 2)
>1.29
1.55
2.95
>6.72
0.17 (n = 5)
0.08
32.1
32.5
32.2
6.5
33.0
33.6
6.7
16.7
4.26
>32.5
6.0
>29.5
34.1
32.7
13.5
15.7
14.6
28.7
CF3
CF3
CF3
CF3
CF3
CF3
OCF3
SO2Me
CF3
CF3
CF3
CF3
CF3
CF3
0.43
0.009 (n = 7)
0.002 (n = 3)
0.004 (n = 2)
0.13 (n = 2)
>1.30
0.060
0.009
0.52
>28.70
H
6-OMe
6-CF3
6-CN
6-CO2Me
6-CO2H
0.13
0.04
1.05
na
a
See footnotes in Table 1.
tent in binding inhibition compared to the 3-, 4- and 6-Me analogs,
Br
4a, 4b and 4d which had a comparable binding inhibition in the
b-c
OH
O
2f
range of 0.14–0.22
three compounds ranged from 0.34 to 1.96
l
M. In addition the anti-HIV-1 activity for these
M. However, as was
l
NH
NH
NBoc
F3C
F3C
15
14
observed for the O-aryl series (Table 3) when the bromine atom
was replaced with a CF3 group the binding inhibition for com-
pounds 4e–4g was enhanced with the IC50 in the range of 0.04–
a
O
O
O
0.06
for all three compounds only the 6-Me substituent 4g displayed
moderate antiviral activity with an IC50 of 0.17 M. However, sub-
lM. Interestingly, although the binding inhibition was similar
d
2g
NBoc
NBoc
F3C
F3C
11
12
l
e, f or g
stitution of an electron withdrawing chloro or cyano substituent at
the 6-postion, 4j and 4p, provided a 19-fold enhancement in anti-
viral potency to an IC50 of 0.009 lM compared to the 6-Me analog
4g. In contrast, the effect of electron donating substituents on the
pyridine ring such as the methoxy group 4n and carboxylic acid
group 4q were detrimental to antiviral activity. Replacing the R
group with a –OCF3 group 4k or a –SO2Me group 4l resulted in
an additional enhancement in binding inhibition (IC50 0.03 and
OR
3a-3j
4e-4j
4m-4r
F3C
13
Scheme 3. Reagents and conditions: (a) 1-bromo-2-(bromomethyl)benzene, Mg, I2,
Et2O; then THF/Et2O, 90%; (b) Pd(OAc)2, BINAP, K2CO3, toluene, 75%; (c) TFA, CH2Cl2;
(d) catechol, TsOH, xylene, reflux, 47 h, 47% over two steps; (e) NaBH4, MeOH, 87%;
(f) NaH, substituted halopyridine, DMF, 90 °C, 44–95%; (g) substituted hydroxy-
pyridine or substituted phenol, Ph3P, DIAD, THF, 48–82%.
0.01 lM) and antiviral potency, IC50 of 0.002 and 0.004 lM, respec-
tively. These compounds were 18–80-fold more potent then 1 in
the inhibition of HIV-1 replication.
Although the O-pyridyl compounds exhibited potent anti-viral
activity the pharmacokinetic properties in rat and dog for a repre-
sentative example, compound 4j, was poor (F% of 20 and 6, respec-
tively) when compared to 1 (Table 5). The poor pharmacokinetic
properties of 4j and related compounds can most likely be attrib-
uted to the high molecular weight (MW 662) and high lipophilicity
(c Log P 6.6) and as a consequence these compounds were not fur-
Having recognized that a substituent on the ring in the O-aryl
series provided an enhancement in both binding inhibition and
antiviral potency we sought to determine the optimal point of sub-
stitution of the O-pyridine ring (Table 4). With the R substituent
equal to bromine we walked the methyl group around the ring
and determined that the 5-Me analog 4c was substantially less po-
Table 5
Pharmacokinetics of 1 and 4j in rat and doga
Compound
Species
Cmax
(
lM)
AUC0–inf (h
l
M)
CL (ml/min/kg)
V (L/kg)
T1/2 (h)
F (%)
1
4j
4j
Rat
Rat
Dog
1.6
0.2
0.1
4.3
2.4
0.5
31.7
141.7
31.7
7.2
15.2
20.8
2.7
1.2
7.7
48
20
6
a
Clearance (CL), volume of distribution (Vdss) and half life (T1/2) calculated following a 10
calculated following solution doses of 100 mol/kg in rat and 12.5 mol/kg in dog.
lmol/kg iv dose in rat and 5 lmol/kg iv dose in dog. Oral bioavailability (F)
l
l

R. Skerlj et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2450–2455
2455
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ther assessed for potential drug-drug interactions (CYP P450 inhi-
bition) or cardiovascular safety (hERG). However, the selectivity of
4j and related analogs was evaluated in Ca2+ flux assays against a
series of other closely related G-protein-coupled receptors
(GPCRs), which included CCR1, CCR2b, CCR4, CXCR1, CXCR2 and
CXCR4, and were found to be non-inhibitory. In addition 4j and
analogs were not cross reactive to the M2 muscarinic receptor.
In conclusion we designed a novel series of antagonists of the
chemokine receptor CCR5 based on inhibition of CCR5 ligand (RAN-
TES) binding that exhibited potent inhibition of R5 HIV-1 (BaL) rep-
lication in PBMC. Given that these compounds had poor
pharmacokinetic properties and two stereogenic centers they were
not further pursued, but the SAR was used to optimize the aniline
series (2e, Table 2), and these results will be reported shortly.
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N. E.; Strizki, J. M.; Baroudy, B. M.; Dan, N. Bioorg. Med. Chem. Lett. 2003, 13,
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References and notes
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18. 3,5-Dichloro-N-(3-(4-((6-cyanopyridin-2-yloxy)(4-trifluoromethyl
phenyl)methyl)piperidin-1-yl)butyl)isonicotinamide: White solid. 1H NMR
(300 MHz, CDCl3) d 0.47–0.78 (m, 3H), 0.92 (m, 7H), 1.19 (m, 2H), 1.51 (m,
2H), 1.69–2.04 (m, 8H), 2.38 (m, 2H), 2.65 (m, 1H), 2.73–2.88 (m, 5H), 3.33 (m,
2H), 3.86 (m, 2H), 5.41 (m, 2H), 6.93 (d, 2H, J = 8.4 Hz), 7.26 (m, 2H), 7.35 (m,
4H), 7.56 (d, 4H, J = 4.5 Hz), 7.65 (m, 2H), 8.59 (s, 2H), 8.61 (s, 2H), 9.03 (d, 1H,
J = 4.8 Hz), 9.12 (d, 1H, J = 4.5 Hz). 13C NMR (CDCl3) d 13.26, 28.52, 28.68, 29.44,
30.09, 20.30, 40.16, 40.23, 41.41, 43.71, 43.80, 51.72, 60.41, 60.48, 80.58,
116.09, 117.09, 122.23, 125.33, 127.57, 129.08, 130.28, 139.50, 143.16, 143.25,
147.66, 147.70, 161.49, 161.56, 162.99. ES-MS m/z 628 (M+Na). Anal. Calcd. for
3. For
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C29H28N5Cl2F3O2: C, 57.43; H, 4.65; N, 11.55; Cl, 11.69; F, 9.40. Found: C, 57.20;
6. Skerlj, R. T.; Bridger, G. J.; Kaller, A.; McEachern, E. J.; Crawford, J.; Zhou, Y.;
Atsma, B.; Langille, J.; Nan, S.; Veale, D.; Wilson, T.; Harwig, C.; Hatse, S.;
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H, 4.65; N, 11.54; Cl, 11.50; F, 9.20.