Evaluation of amide replacements in CCR5 antagonists as a means to increase intrinsic permeability. Part 2: SAR optimization and pharmacokinetic profile of a homologous azacyle series

Article abstract of DOI:10.1016/j.bmcl.2010.08.118

Replacement of a secondary amide with a piperidine or azetidine moiety in a series of CCR5 antagonists led to the discovery of compounds with increased intrinsic permeability. This effort led to the identification of a potent CCR5 antagonist which exhibited an improved in vivo pharmacokinetic profile.

Full text of DOI:10.1016/j.bmcl.2010.08.118

Bioorganic & Medicinal Chemistry Letters 20 (2010) 6802–6807
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Evaluation of amide replacements in CCR5 antagonists as a means
to increase intrinsic permeability. Part 2: SAR optimization
and pharmacokinetic profile of a homologous azacyle series
⇑
,
Jutta Wanner a, , Lijing Chen a, Rémy C. Lemoine a, Rama Kondru a, , Andreas Jekle b,à, Gabrielle Heilek b,
André deRosier b, Changhua Ji b, Pamela W. Berry c,§, David M. Rotstein a
a Department of Medicinal Chemistry, Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA 94304, USA
b Department of Viral Diseases, Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA 94304, USA
c Department of DMPK, Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA 94304, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Replacement of a secondary amide with a piperidine or azetidine moiety in a series of CCR5 antagonists
led to the discovery of compounds with increased intrinsic permeability. This effort led to the identifica-
tion of a potent CCR5 antagonist which exhibited an improved in vivo pharmacokinetic profile.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 14 June 2010
Revised 22 August 2010
Accepted 24 August 2010
Available online 18 September 2010
Keywords:
CCR5 antagonist
HIV entry inhibition
Permeability
CCR5 and its endogenous ligands RANTES, MIP1-
a
, and MIP1-b
hydrophobe 1 tolerating a limited level of polarity, and a (het-
ero)aryl group in the eastern part of the molecule (the head).5
are implicated in organ transplant rejection as well as in the path-
ophysiology of inflammatory diseases such as rheumatoid arthritis
(RA). Additionally, in 1996 it was discovered that CCR5 acts as the
co-receptor for cellular entry of R5-tropic HIV-1 viruses, which
predominate during the early stages of viral infection.1 Since indi-
viduals who are homozygous for the CCR5 delta 32 mutation
(which results in non-functional CCR5) are resistant to HIV infec-
tion and experience less severe symptoms of RA,2 CCR5 presents
an exciting target for the development of small molecule antago-
nists for the treatment of HIV, inflammatory diseases and/or to
control transplant rejection.3
F
F
tail hydrophobe 1
O
H
HN
N
O
N
tail hydrophobe 2
(hetero)aryl head
H
1
F
N
N
R
We previously introduced a new series of CCR5 antagonists
exemplified by compound 1 (Fig. 1).4
Compound 1 contains the four pharmacophores found in many
of the series reported in the literature: a tertiary basic amine, two
hydrophobes in the western part of the molecule (the tail), with
4-, 5-, 6-membered
rings
4-, 6-membered
rings
R
N
N
H
H
N
N
O
O
N
N
⇑
Corresponding author. Tel.: +1 973 235 2737.
E-mail address: jutta.wanner@roche.com (J. Wanner).
Present address: Discovery Chemistry, Hoffmann-La Roche Inc., Nutley, NJ 07110,
USA.
H
H
Ar
Ar
2
3
X
X
gem-disubstituted azacycle series
homologous azacycle series
à
Present address: NovaBay Pharmaceuticals, 5850 Horton street, Emeryville, CA
94608, USA.
Figure 1. Compound 1, a representative example of our CCR5 antagonist series, the
gem-disubstituted azacycle series (2), and the homologous piperidine and azetidine
azacycle series (3).
§
Present address: DMPK, Hoffmann-La Roche Inc., 340 Kingsland street, Nutley NJ
07110, USA.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.08.118

J. Wanner et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6802–6807
6803
Not unexpectedly, based on the physicochemical properties of
Ph
Ph
Ph
Ph
the series (molecular weight above 500, a number of hydrogen-
bonding functionalities, and a basic amine), most compounds in
this series showed borderline membrane permeability6 (intrinsic
permeability7 in our assay ranging from 2 to 5 Â 10À6 cm/s) and
were subject to transport by the efflux pump P-glycoprotein (P-
gp). In some cases, the low permeability translated into poor phar-
macokinetic profiles (low oral bioavailability, high clearance). A
similar challenging preclinical pharmacokinetic profile was re-
ported for maraviroc (SelzentryÒ), the first FDA-approved small
molecule HIV entry inhibitor.8 We reasoned that by (re)moving
the tail primary amide we might be able to improve the intrinsic
permeability by reducing the desolvation energy cost (i.e., leading
to a decrease in the membrane/solvent partition coefficient) and/or
by reducing the affinity for P-gp.9
Ph
N
Ph
N
O
N
(c)
(a)
(b)
OEt
O
9
10
N
X
X
Boc
Boc
N
N
O
(f)
(d)
(e)
OEt
O
8
X
X
Scheme 2. Synthesis of compounds in the azetidine series. Reagents and condi-
tions: (a) PhMgBr, 3-F-PhMgBr or 3,5-diF-PhMgBr, benzene, 0 °C to rt, overnight; (b)
aqueous NaOH, EtOH, 60 °C, 50–75% over two steps; (c) (diethoxy-phosphoryl)-
acetic acid ethyl ester, NaH, THF, 0–60 °C, overnight, 90–95%; (d) H2 (1 atm), 20%
Pd(OH)2, EtOH, RT, 24 h, >95%; (e) Boc2O, NaOH, THF/H2O, rt, overnight, 80–90%.
In an earlier publication we presented a first set of compounds
in which the tail amide of our initial series had been replaced by
gem-disubstituted azacycles (Fig. 1, 2).10 These compounds, as
hypothesized, showed improved intrinsic permeability in vitro;
unfortunately, due to the lack of metabolic stability, no in vivo ef-
fect of the improvement could be demonstrated.
In this paper, we describe the optimization of a parallel series in
which the tail amide was replaced with homologous piperidine
and azetidine moieties (Fig. 1, 3). These replacements were attrac-
tive not only because they allowed us to test our hypothesis, but
also because similar groups were described previously in the
CCR5 literature.11
piperidine-1-carboxylic acid tert-butyl ester 4 via a Horner–Wads-
worth–Emmons reaction. Hydrogenation of the double bond fol-
lowed by selective reduction of the racemic ester yielded the key
racemic aldehyde intermediate 5. We were able to separate both
enantiomers of the ester and in some cases to use the enantiome-
rically pure fractions in the subsequent chemical steps. The final
compounds were prepared according to two general procedures.
In the first procedure, aldehyde 5 was treated under reductive ami-
nation conditions with the benzyl-protected bispyrrolidine core
6.12 Removal of the benzyl group was followed by acylation of
the free amine. In the second procedure, the fully elaborated sys-
tem 7 was employed in the reductive amination reaction. In both
cases, the completion of the synthesis involved deprotection of
the tail amine and treatment with acyl chlorides, sulfonyl chlo-
rides, isocyanates, chloroformates or alkyl triflates.
The azetidine-containing compounds were synthesized using
the same general procedure, but using aldehyde 8 instead of alde-
hyde 5. Aldehyde 8 was prepared from commercially available 1-
benzhydryl-azetidine-3-carbonitrile 9 according to the route out-
lined in Scheme 2.
Grignard addition with either phenylmagnesium bromide, 3-
fluorophenylmagnesium bromide or 3,5-difluorophenylmagne-
sium bromide, and hydrolysis of the resulting imine gave the ke-
tone intermediates 10, which were then employed in a Horner–
Wadsworth–Emmons reaction. Hydrogenation of the double bond
and concomitant removal of the benzhydryl group gave the free
amine, which was Boc protected. Selective reduction of the ethyl
esters yielded the racemic aldehydes 8. Reductive amination and
tail piece introduction were carried out following the steps de-
scribed in Scheme 1.
The fluoro analogs in the piperidine subset were synthesized
starting from known commercially available Boc-protected 4-cya-
no-piperidine in a sequence analogous to the one described in
Scheme 2 for the azetidine subset.
To explore the largest chemical space possible, we prepared an
array of ureas, carbamates, sulfonamides, amides, and fluoroalkyl-
amines. Unless specified, compounds in both subsets were pre-
pared as racemic mixtures. In this initial array the head
heteroaryl was kept constant (4,6-dimethyl-pyrimidine-5-yl). The
compounds were tested as inhibitors of RANTES binding, of cell fu-
sion, and of viral entry (Table 1).
The most potent compounds of this array contained small fluo-
rinated alkyl chains (12–15) or sulfonamides (17) in the piperidine
subset and sulfonamides in the azetidine subset (24–27). Urea, car-
bamate and amide substituents were not tolerated and resulted in
loss of cell–cell fusion inhibition (11, 16, 18, 22 and 23), even if the
As shown in Scheme 1, the synthesis of the piperidine-contain-
ing compounds began with elaboration of the known 4-benzoyl-
Boc
Boc
Boc
N
N
N
(a)
(b)
CO2Et
CO2Et
O
4
Boc
Boc
H
6
N
N
HN
N
H
O
Bn
H
N
(c)
N
Bn
(d)
H
5
H
7
(d)
(b), (e)
HN
H
Ar
N
H
N
O
R
N
Boc
N
H
N
N
Ar
Ar
N
H
H
O
O
3
(f), (g)
Scheme 1. General synthetic methods for the preparation of compounds in the
piperidine sub-series. Reagents and conditions: (a) (diethoxy-phosphoryl)-acetic
acid ethyl ester, NaH, THF, 0–60 °C, overnight, 90–95%; (b) H2 (1 atm), 20% Pd(OH)2,
EtOH, rt, 24 h, >85%; (c) DIBAL-H, CH2Cl2, À78 °C to rt, overnight; Tempo, bleach,
CH2Cl2/H2O, 70–80% over two steps; (d) NaBH(OAc)3, HOAc, CH2Cl2, rt, 2 h
overnight, 47–73%; (e) ArCOOH, EDCI, HOBt, Et3N (or DIPEA), CH2Cl2, rt, overnight,
30–80%; (f) HCl 4 M in dioxane, CH2Cl2, RT, 2 h; (g) RCOOH, EDCI, HOBt, Et3N,
CH2Cl2, rt, overnight, or RCOCl (or RSO2Cl, TfOCH2CF3, RCNO, or RCOCl) Et3N, CH2Cl2,
0 °C to rt, overnight, 50%.

6804
J. Wanner et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6802–6807
Table 1
RANTES binding inhibition,14 cell–cell fusion inhibition,15 and antiviral activity16 of representative piperidine- and azetidine-tail compounds
R
N
R
N
H
H
N
N
O
O
N
N
H
X
H
X
N
N
P
A
N
N
a
Compd
Tail
P
X
R
Binding IC50 (nM)
Cell–cell fusion
inhibition IC50 (nM)
Antiviral activity
IC50 (nM)
a
a
N
b
11
H
>500
>5000
—
O
CF3
12
13
14
15
P
P
P
P
H
17
27
35
25
34
137
11
64
55
14
20
CHF2
CHF2
CHF2
O
H
3-F
3,5-di-F
19
b
16
P
H
102
744
—
O
S
17
18
19
P
P
P
H
H
H
47
32
72
99
>5000
>5000
48
O
O
b
—
O
b
—
O
O
b
20
21
P
H
H
68
2819
—
b
CF3
A
>500
>5000
—
b
22
A
H
207
2832
—
O
b
23
24
A
A
H
H
>500
23
>5000
93
—
O
S
100
103
156
90
O
O
O
O
O
O
O
O
25
26
27
A
A
A
H
40
39
35
313
30
S
S
S
3-F
3,5-di-F
63
a
Values are means of at least two experiments.
Not determined.
b
compounds inhibited RANTES binding. As has been observed by
others,13 in some cases RANTES binding inhibition did not translate
into functional activity (cell fusion, antiviral) due to different con-
formational change requirements for binding inhibition and func-
tional activity. In the piperidine subset, for example, carbamate
16 and amide 18 showed RANTES binding inhibition (102 nM
and 32 nM, respectively), but essentially no cell–cell fusion inhibi-
tion was observed. In general, we used the RANTES binding inhibi-
tion assay and the cell fusion assay as first activity screens, and
used the functional antiviral assay to compare compounds. It is
worth noting that we never encountered a compound inactive in
the binding assay and active in the functional assays.
Earlier SAR suggested that antiviral activity could be improved
by the introduction of halogen atoms in the aromatic ring of
tail hydrophobe 2. In the case of the homologous piperidine and
azetidine sub-series, we did not observe any significant activity
effect (compounds 13 and 14 vs 12 and compounds 26 and 27 vs
25).
With the encouraging potencies observed for the sulfonamide
analogs in either subset (17, 24–27), we focused on the optimization

J. Wanner et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6802–6807
6805
Table 2
RANTES binding inhibition,14 antiviral activity16 and metabolic stability of piperidine- and azetidine-sulfonamides
R
N
R
N
H
H
N
N
O
O
N
N
H
X
H
X
N
N
P
A
N
N
Compd
Tail
X
R
Binding inhibition
IC50 (nM)
Antiviral activity
IC50 (nM)
HLMb
a
a
25
28
A
A
H
H
40
52
103
40
S
S
O
O
O
O
c
>625
—
29
A
H
22
31
294
S
S
O
O
O
O
CF3
c
30
31
32
P
P
P
H
H
H
48
27
25
207
71
—
c
—
S
S
O
O
O
O
39
90
c
33
P
H
H
23
59
—
S
S
S
O
O
O
O
O
O
34
35
P
P
34
44
43
16
41
67
3-F
H
c
36
P
38
6
—
S
O
O
a
b
c
Values are means of at least two experiments.
Human liver microsomal intrinsic clearance (ll/min/mg protein); in our assay, values P35 ll/min/mg protein were considered to be high clearance values.
Not determined.
of antiviral potency by incorporating different sulfonamide tail
pieces. Representative compounds are shown in Table 2.
methyl-pyran-2-one (39) did not improve antiviral potency, the
incorporation of the 4,6-dimethyl-pyridine-2-carbo-nitrile17 head
piece increased the antiviral potency approximately 10-fold (com-
pound 40, 4 nM, compared to compound 34, 43 nM). However,
compound 40 lacked metabolic stability in our in vitro human liver
microsome assay and was not further profiled.
We prepared both enantiomers of compounds 34 and 35 using
enantiomerically pure aldehyde 5. It was found that the activity re-
sided fully in one enantiomer as shown in Table 4. We did not
determine the absolute stereochemistry of the active enantiomers
41 and 43.
In order to evaluate our hypothesis that the intrinsic permeabil-
ity could be improved by removing the tail primary amide portion,
we tested representative compounds in both subsets in a 21-day
Caco-2 permeability assay in the presence and absence of the P-
gp inhibitor elacridar.
Most of the compounds synthesized possessed at least twofold
higher intrinsic permeability7 values than the representative pri-
mary-amide-tail compound 1, as shown in Table 5. This trend
was shown to be general, and no correlation between c log P, log D
or polar surface area and the obtained AB fluxes (with or without
In the azetidine subset, larger sulfonamide tail pieces led to
compounds with higher potencies, as seen in analog 29, which
showed an antiviral IC50 of 31 nM. However, we were not able to
increase antiviral activity further by modifying the azetidine sul-
fonamide substituent. In the piperidine subset, with the exception
of the trifluoro ethane group, compound 30, various sulfonamide
groups (31–36) were well tolerated, but did not significantly im-
prove antiviral activity. The best substituent in this sub-series
was the phenyl sulfonamide (36). Unfortunately, the phenyl substi-
tuent introduced cytochrome P450 inhibition liabilities. Various
modifications such as incorporation of heteroatoms and substitu-
ents did not result in compounds with better profiles (data not
shown). In this array, 34 was one of the most active and metabol-
ically stable compounds and was used as starting point for the
preparation of a set of compounds in which the head piece was
varied (Table 3).
The incorporation of sulfonamides in the head region was not
tolerated, as seen with compounds 37 and 38. We then introduced
two of the best heads in our original series. While the 4,6-di-

6806
J. Wanner et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6802–6807
Table 3
Table 5
RANTES binding inhibition,14 cell–cell fusion inhibition,15 antiviral activity16 and
metabolic stability of piperidine methylsulfonamides
Apparent fluxes in 21-day Caco-2 assaysa with or without elacridar and apparent
efflux ratio
Compd Papp: ABb 21-day
Caco-2 without
Papp: AB 21-day
Efflux ratio BAd/AB 21-
day Caco-2 without
elacridar
O
S O
Caco-2 with 2
elacridar
lM
N
elacridarc
H
N
1
29
34
40
41
43
0.22
1.4
0.87
0.85
0.5
5.41
12.40
16.50e
18.10
10.20
12.60
55.38
11.30
24.10
30.00
42.90
41.40
O
N
H
Ar
Compd
R
Binding
Cell–cell
fusion
inhibition
Antiviral
activity
IC50 (nM)
HLMb
0.5
inhibition
a
b
c
Mass recovery was within set target values in all cases.
Apparent apical to basolateral fluxes (10À6 cm/s).
a
a
IC50 (nM)
a
IC50 (nM)
Permeability category for Caco-2 assay (0–1, low; 1–10, medium; >10, high).
Apparent basolateral to apical fluxes (10À6 cm/s).
d
e
O
S
Papp: AB 21-Caco-2 in the presence of 1 lM elacridar.
N
34
37
38
34
104
215
57
43
41
N
Cl
O
O
O
O
Table 6
Key properties of 43
c
2173
4123
>625
—
Antiviral activity
hERGb IC20
M)
Intrinsic clearancea
L/min/mg protein)
Intrinsic
IC50 (nM)
(
l
(l
permeabilityc
a
Cl
S
c
c
—
—
RLM
40
DLM
18
HLM
60
CN
O
16
15.4
12.6
O
a
Values are means of at least two experiments.
Measured at 37 °C.
b
c
O
N
39
40
27
31
8
37
63
Unit: 10E-6 cm/s; see also Ref. 7.
O
1.2
4
162
Table 7
CN
Pharmacokinetic parameters of 43 in rata and doga
a
b
c
Values are means of at least two experiments.
Rat
Dog
Human liver microsomal intrinsic clearance (
l
l/min/mg protein).
Dose
Dose
Not determined.
Oral: 10 mg/kg
IV: 1 mg/kg
F = 6.6%
Oral: 5 mg/kg
IV: 1 mg/kg
F = 96%
Cl = 40 mL/min/mg
IV T1/2 = 0.37 h
Cmax = 110 ng/mL
Cl = 31 mL/min/kg
IV T1/2 = 4 h
Cmax = 1300 ng/mL
Table 4
RANTES binding inhibition14 and antiviral activity16 of both enantiomers of 34 and 35
a
O
Values are means of two experiments.
S O
N
H
N
Compound 43 was selected for further evaluation. A summary
of key properties is shown in Table 6. Compound 43 had good anti-
viral potency, was not an inhibitor of the hERG18 potassium ion
channel and the cytochrome P450 CYP enzymes,19 and showed a
medium microsomal stability.20 The improved intrinsic permeabil-
ity of 43 together with its moderate in vitro clearance translated
into an appealing pharmacokinetic profile in rat and dog, with an
oral bioavailability of 7% and 94%, respectively (Table 7). Addition-
ally, an in-house comparison showed that 43 maintained higher
exposures compared to maraviroc in both species (Fig. 2).
In summary, we described the synthesis and optimization of
azacyclic CCR5 antagonists. Careful tuning of the head and tail sub-
stituents resulted in the identification of potent compounds. Addi-
tionally, compounds of this azacyclic series showed increased
intrinsic permeability compared to the original amide tail series.
The improved intrinsic permeability of 43 together with its moder-
ate in vitro clearance translated into an appealing pharmacokinetic
profile.
O
N
H
X
N
N
Compound
X
Binding inhibition
Antiviral activity
IC50 (nM)
a
a
IC50 (nM)
Enantiomer 1 (41)
Enantiomer 2 (42)
Enantiomer 1 (43)
Enantiomer 2 (44)
H
H
F
25
>500
32
42
>5000
17
b
F
>500
—
a
Values are means of at least two experiments.
Not determined.
b
elacridar) could be established. It is also noteworthy to point out
that the AB apparent fluxes (without elacridar) also improved at
least twofold, with flux values in some cases moving from the
low permeability category in our assay to the medium category.
The efflux ratios, however, remained relatively high in the in-vitro
assay, indicating that under the assay conditions P-gp might trans-
port the compounds quite efficiently despite the increase in intrin-
sic permeability.
Acknowledgements
The authors thank Dr. Counde O’Yang for his support and
helpful suggestions and Marquis Cummings for chiral HPLC
separations.

J. Wanner et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6802–6807
6807
100
10
1
1000
Dog PK P
Rat PK
10 mg/kg PO
43
43
maraviroc
100
maraviroc
10
1
0.1
0.1
0
2
4
6
8
0
6
12
18
24
Time (h)
Time (h)
Figure 2. Dose-normalized exposures; (a) rat PO PK comparison of 43 (5 mg/kg) and maraviroc (5 mg/kg); (b) dog PO PK comparison of 43 (5 mg/kg) and maraviroc (10 mg/
kg). Values are means of two experiments.
11. (a) Tucker, H.; Oldfield, J.; Brown, D. WO Patent 067,385.; (b) Cumming, J. G.;
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