Synthesis and evaluation of 2-phenyl-1,4-butanediamine-based CCR5 antagonists for the treatment of HIV-1

Article abstract of DOI:10.1016/j.bmcl.2011.01.030

We describe the synthesis and potency of a novel series of N-substituted 2-phenyl- and 2-methyl-2-phenyl-1,4-diaminobutane- based CCR5 antagonists. Compounds 7a and 12f were found to be potent in anti-HIV assays and bioavailable in the low-dose rat PK model.

Full text of DOI:10.1016/j.bmcl.2011.01.030

Bioorganic & Medicinal Chemistry Letters 21 (2011) 1394–1398
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and evaluation of 2-phenyl-1,4-butanediamine-based CCR5
antagonists for the treatment of HIV-1
Matthew D. Tallant a, , Maosheng Duan a, George A. Freeman a, Robert G. Ferris b, Mark P. Edelstein b,
⇑
Wieslaw M. Kazmierski a, Pat J. Wheelan c
a Department of Chemistry, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709, USA
b Department of Virology, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709, USA
c ID DMPK, Infectious Diseases Center for Excellence in Drug Discovery, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe the synthesis and potency of a novel series of N-substituted 2-phenyl- and 2-methyl-2-
phenyl-1,4-diaminobutane- based CCR5 antagonists. Compounds 7a and 12f were found to be potent
in anti-HIV assays and bioavailable in the low-dose rat PK model.
Received 19 November 2010
Revised 5 January 2011
Accepted 7 January 2011
Available online 11 January 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
CCR5
HIV-1
Diaminobutane
Tropane
Benzimidazole
The Chemokine Receptor R5 (CCR5) is a member of the 7TM
G-protein coupled receptor (GPCR) family and, with CD4, serves
as a co-receptor for HIV-1 infection of host cells. CCR5 antagonism
enabled a novel mechanism to inhibit HIV-1 infection and thus it
became an attractive target pursued by the pharmaceutical indus-
try.1 Significant research and development efforts have led to sev-
eral small molecule clinical candidates2 and one FDA approved
drug, Maraviroc.3 Additional CCR5 antagonists with improved
potency and pharmacokinetics suitable for daily dosing, are needed
and offer promise as potential new components of the anti-HIV
combination therapy.
Our laboratories have recently reported the synthesis and
structure–activity relationship of a series of 4,4-disubstituted
piperidine carboxamide CCR5 antagonists exemplified by 1, which
have demonstrated activity against HIV-1 (Fig. 1).4 Herein, we wish
to disclose further investigation of novel series 2-methyl-2-phe-
nyl-1,4-diaminobutane (MDAB) and 2-phenyl-1,4-diaminobutane
(DAB), represented by 2 (Fig. 1). Although the 1,4-diaminobutane
scaffold has been previously explored in CCR5 and was demon-
We first examined so far unreported influence of tropane moi-
ety on compound antiviral potency in the 1,4-diaminobutane
scaffold series.
The synthesis of racemic, 2-phenyl-DAB analogs 7a–i, 11a–c,
12a–f and 14a–f is described below. Analoging at either amine
center was conveniently carried out using separate convergent
syntheses from commercially available diethyl (phenylmethylid-
ene)propanedioate. Analogs 7a–i were prepared in six steps
(Scheme 1) by conjugate addition of potassium cyanide in ethanol
to afford the 3-cyano-3-phenylpropanoate ester (3) which was
converted to the corresponding aldehyde (4) in a two-step proce-
dure by reduction with lithium borohydride in refluxing THF fol-
lowed by oxidation using Dess–Martin periodinane. The aldehyde
was reacted with endo-1-(8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-
1H-benzimidazole (6)4 under reductive amination conditions and
O
R2
N
strated to potently displace MIP-1a in the CCR5 radioligand bind-
N
R
N
N
R1
N
ing assay, compounds turned out to be only modest inhibitors of
N
X
HIV in cellular assays.5
R3
H
X = C(O), SO2
2
H(F)
1
⇑
Corresponding author. Fax: +1 919 483 6053.
E-mail address: matthew.d.tallant@gsk.com (M.D. Tallant).
Figure 1. 4,4-Disubstituted piperidine 1 and diaminobutane (DAB) scaffold 2.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.01.030

M. D. Tallant et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1394–1398
1395
O
R
NH
CN
O
O
O
b, c
a
O
a, 13a or 13b
then b, c
N
N
4
N
N
O
3
O
CN
14
NH2
d, e
N
N
N
N
N
H
HN
4
N
5
HN
H
N
R1
N
H
N
N
R2
endo-13a
N
exo-13b
f, g, h,
i or j
N
N
Scheme 3. Reagents and conditions: (a) NaBH(OAc)3, CH2Cl2, rt, 18 h, 93%; (b)
Raney-Ni, H2 (60 psi), EtOH, concd NH4OH, rt, 18 h, 95%; (c) RCO2H/HATU/iPr2NEt/
CH2Cl2 or RSO2Cl/iPr2NEt/CH2Cl2, rt, 1–2 h.
H
7b,c,e-i
k, l, m
5
7a,d
then f or g
subjected to standard acylating conditions to afford the corre-
sponding amides, sulfonamides and sulfonyl ureas 7a–i.
The synthesis of analogs 11a–c (Scheme 2) began with the
hydrogenation of 3-cyano-3-phenylpropanoate (3) over palladium
on carbon in ethanol and aqueous HCl to give 3-phenyl-4-amino
ester (8) which was then treated with phenylsulfonyl chloride
and Hunig’s base at ambient temperature. The resulting ethyl
3-phenyl-4-[(phenylsulfonyl)amino]butanoate was reduced to
the corresponding alcohol (9) with lithium borohydride. Upon oxi-
dation of the alcohol, it was discovered that the resulting aldehyde
undergoes spontaneous intramolecular cyclization with the sulfon-
amide to give the five-membered N,O-aminal which was highly
unreactive to reductive amination conditions. Hence, we fashioned
an orthogonally-protected synthesis in which alcohol (9) is first
protected as the O-tert-butyldimethylsilyl ether and subsequently
treated with sodium hydride and di-tert-butyldicarbonate in DMF
at room temperature which converted the 1-phenylsulfonamide
into its N-Boc derivative. Silyl deprotection was achieved with
TBAF in THF and the primary alcohol oxidized to the aldehyde
(10) in 40% yield over four steps. Intermediate 10 was subjected
to standard reductive amination conditions with tropane imida-
zoles,6 to give the corresponding 2-phenyl-DAB analogs 11a–c
after Boc-deprotection with TFA in dichloromethane. Additionally,
4-substituted piperdines and 2-substituted octahydropyrrolo[3,4-
c]pyrroles were also condensed with (10) to give analogs (12a–f).
Analogs 14a–f were prepared in a similar fashion to 7a–f
(Scheme 3). Hence, aldehyde (4) was treated with endo- and exo-
tropane-1,2,4-triazoles (13a) and (13b)7 in the presence of sodium
triacetoxyborohydride followed by Raney-Nickel reduction of the
nitrile. The resulting amine was then converted to amides and sul-
fonamides 14a–f using standard chemistry.
Finally, 2-methyl-2-phenyl-1,4-diaminobutanes 16a–f were
prepared as racemates in five steps from ethyl 3-cyano-3-phenyl-
butanoate8 (Scheme 4). Low-temperature, DIBAL reduction of the
ethyl ester afforded the aldehyde which was subsequently treated
with either endo-tropane (6) or exo-tropane (13b) under the stan-
dard reductive amination conditions. Due to the hindered nature of
the nitrile, hydrogenation required elevated temperature (50 °C)
but proceeded in high yield and gave MDAB intermediate 15.
Treatment of the primary amine with phenylsulfonyl chloride/Hu-
nig’s base or 4,4-difluorocyclohexanecarboxylic acid/HATU affor-
ded the corresponding sulfonamides and amides (16a–f),
respectively. These, in turn, could be N-methylated with NaH/
MeI with variable yield.
N
N
HN
H
endo-6
Scheme 1. Reagents and conditions: (a) KCN, EtOH–H2O, 70 °C, overnight, 73%; (b)
LiBH4, THF, reflux, 2 h, 59%; (c) Dess–Martin periodinane, CH2Cl2, rt, 2 h, 89%; (d)
NaBH(OAc)3, endo-6, CH2Cl2, rt, 18 h, 70%; (e) Raney-Ni, H2 (50 psi), EtOH/concd
NH4OH (6:1), rt, 18 h, 99%; (f) 4,4-difluorocyclohexanecarboxylic acid, HATU,
iPr2NEt, CH2Cl2, rt, 2 h, 56%; (g) RSO2Cl, iPr2NEt, CH2Cl2, rt, 37–74%; (h) morpholine-
4-sulfonyl chloride, ACN, iPr2NEt, 5 h, 80 °C, 70–72%; (i) Ac2O, iPr2NEt, CH2Cl2, rt,
83%; (j) iPr2NEt, P(O)(OMe)2Cl, CH2Cl2, rt, 43%; (k) o-NosCl, iPr2NEt, CH2Cl2, 74%; (l)
(i) NaH, THF, rt; (ii) MeI, 80%; (m) LiOH, HSCH2CO2H, DMF, rt, 2 h, 100%.
H2N
O
b,c
a
3
O
8
d, e, f
Boc
H
N
N
then g
S
O
S
OH
O
O
O
O
9
10
h, i
H
10
10
N
S
N
Het
O
O
11a-c
j
H
then i
N
Het
S
O
O
12a-f
Scheme 2. Reagents and conditions: (a) Pd/C, H2 (60 psi), EtOH, concd HCl, rt,
overnight, 45%; (b) PhSO2Cl, iPr2NEt, CH2Cl2, rt, 18 h, 92%; (c) LiBH4, THF, 65 °C, 2 h,
100%; (d) TBSCl, DMAP, ImH, CH2Cl2, 30 min rt, 88%; (e) (i) DMF, NaH; (ii) Boc2O, rt,
1 h, 55%; (f) THF, TBAF, AcOH, rt, 18 h, 100%; (g) DMP, CH2Cl2, 2 h, rt, 82%; (h)
tropanes corresponding to entries 11a–c in Table 2, NaBH(OAc)3, CH2Cl2, rt; (i) TFA,
CH2Cl2, rt, 3 h; (j) amines corresponding to entries 12a–f in Table 2, NaBH(OAc)3,
CH2Cl2, rt.
All synthesized compounds were tested for antiviral activity in
the HOS cell assay and selected compounds were tested in the PBL
cell assay against the Ba-L strain.9 Structure–activity relationship
of analogs 7a–i is shown in Table 1. Amine functionalization of
the nitrile hydrogenated over Raney-Nickel catalyst in the pres-
ence of concentrated ammonia to afford the 2-phenyl-1,4-diamin-
obutane (5) in good overall yield. The primary amine was then

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M. D. Tallant et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1394–1398
Table 2
H2N
Inhibitory potencies of 11a–c and 12a–f (synthesized according to Scheme 2) in the
HOS and PBL cell assays
O
CN
a, b, c
O
N
Het
Compdsa Heterocycle
HOSb
IC50
PBLb
M) IC50
c
c
(l
(l
M)
15
R2
N
NDd
ND
R1
exo-11a
0.117
0.038
N
N
d or e
then f
N
N
Het
endo-11b
N
N
16
N
Scheme 4. Reagents and conditions: (a) DIBAL-H, THF, À78 °C, 1 h, 19%;
(b)NaBH(OAc)3, 6 or 13b, CH2Cl2, rt, 18 h; 85%; (c) Raney-Ni, H2 (50 psi), EtOH,
concd NH4OH, 50 °C, 18 h, 90%; (d) HATU, difluorocyclohexylcarboxylic acid,
iPr2NEt, CH2Cl2, rt, 18 h, 72%; (e) PhSO2Cl, iPr2NEt, CH2Cl2, rt, 18 h, 73%; (f) NaH,
THF or DMF then MeI, 7–75%.
endo-11c
0.003
0.088
0.001
ND
N
O
N
N
N
12a
Ph
N
Table 1
Inhibitory potencies of 2-phenyl DAB analogues 7a–i (synthesized according to
Scheme 1) in the HOS and PBL cell assays
N
N
12b
0.989
ND
Compdsa R1
R2
HOSb IC50
M)
PBLb IC50
M)
c
c
N
N
(
l
(l
Ph
N
O
O
S
S
N
N
7a
Me 0.008
0.06
12c
5.025
0.045
ND
N
O
O
7b
7c
H
H
0.065
0.016
0.112
0.161
12d
0.043
N
N
N
N
O
O
S
N
N
H2N
12e
0.362
0.008
ND
O
O
O
H
O
NDd
O
N
7d
7e
Me 0.520
S
F
Ph
O
12f
0.001
N
F
F
H
O
a
b
c
All values refer to racemic compounds.
For a description of the HOS and PBL antiviral assays, see Ref. 9.
IC50 values (n P 2 for HOS and n P 3 for PBL) have a standard error usually less
H
0.411
ND
F
than 20%, with assay-to-assay variability usually less than 25% for the standard
compound (aplaviroc).
O
d
Not determined.
S
7f
H
H
0.023
0.013
0.099
ND
O
O
itors are more potent than respective carboxamides. Secondly, as
can be seen by a comparison of 7b–f and 7e–h the size of the ter-
minal substituent has relatively little effect on potency within each
series, the values were observed to be within 2–3-fold between the
sulfonamide and carboxamide series. Another noteworthy obser-
vation is the effect of N-methyl substitution. In the sulfonamide
series, a significant improvement in potency is seen in N-methyl-
ated 7a compared to non-methylated 7b. However, a comparison
of 7d and 7e shows that methylation has no discernable effect in
the carboxamide series.
S
7g
N
O
O
O
7h
7i
H
H
0.866
0.077
ND
ND
O
P
O
O
a
b
c
All values refer to racemic compounds.
For a description of the HOS and PBL antiviral assays, see Ref. 9.
IC50 values (n P 2 for HOS and n P 3 for PBL) have a standard error usually less
Table 2 shows selected, representative results of the effect of
various changes to the right side N-terminal of the 2-phenyl DAB
series. Replacement of the endo-tropane benzimidazole with its
exo-tropane counterpart (example 11a) gives only a modest de-
crease in potency (ꢀ2-fold). 3-Imidazolopyridine in 11b is also tol-
erated. Particularly noteworthy is the high potency of 11c,
obtained when benzimidazole is replaced with 5-acetyl-2-
methyl-4,5,6,7-tetrahydro-imidazo[4,5-c]pyridine. In general,
than 20%, with assay-to-assay variability usually less than 25% for the standard
compound (aplaviroc).
d
Not determined.
the N-terminal of the 2-phenyl-DAB series reveals three trends.
First, sulfonamide, sulfonyl urea and phosphoramide-based inhib-

M. D. Tallant et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1394–1398
1397
Table 3
Table 4
Inhibitory potenciesof 14a–f (synthesized according to Scheme 3) in the HOS cell
Inhibitory potencies of 16a–f (synthesized according to Scheme 4) in HOS and PBL cell
assay
assays
Compdsa
R
endo/exo
endo
HOSb IC50
0.480
(
lM)
Compdsa R1
R2 Heterocycle
HOSb
IC50
PBLb
M) IC50
c
c
c
(
l
(l
M)
O
S
O
O
O
N
14a
O
S
S
S
endo-16a
Me
0.009
0.124
0.578
0.001
NDd
ND
N
O
O
O
O
S
N
14b
14c
exo
0.146
0.866
O
endo-16b
exo-16c
H
N
O
O
endo
N
F
F
H
F
F
N
N
O
O
O
N
14d
exo
9.735
N
endo-16d
Me
0.235
0.249
0.583
ND
ND
ND
F
F
O
N
N
14e
14f
endo
endo
>20
>20
F
endo-16e
exo-16f
H
F
F
F
O
N
H
N
N
F
a
b
c
All values refer to racemic compounds.
For a description of the HOS antiviral assay, see Ref. 9.
IC50 values (n P 2) have a standard error usually less than 20%, with assay-to-
F
a
b
c
All values refer to racemic compounds.
For a description of the HOS and PBL antiviral assays, see Ref. 9.
IC50 values (n P 2 for HOS and n P 3 for PBL) have a standard error usually less
assay variability usually less than 25% for the standard compound (aplaviroc).
than 20%, with assay-to-assay variability usually less than 25% for the standard
compound (aplaviroc).
d
replacement of the tropane ring with piperdine was poorly toler-
ated, as can be seen from a comparison of 7b to 12e. However, po-
tency comparable to the tropane series of Table 1 was seen from
the 2-ethyl-4-(phenylmethyl)-imidazole (12d) and 1-methyl-3-
(phenylmethyl)-pyrazole (12a) substituents. The bicyclic octahy-
dropyrrolo[3,4-c]pyrrole ring also shows promise as can be seen
by example 12f which gave 8 nM in the HOS assay. Piperdine is
presumed to be inferior to tropane due to the lack of rigidity of
the central ring system which imparts a degree of conformational
restraint to the molecule. Table 3 details the results observed when
the tropane benzimidazole is replaced with 3-methyl-5-isopropyl-
1,2,4-triazole. In all cases, the triazole was found to be suboptimal
for the 2-phenyl DAB series. Despite the poor results for these ana-
logs, some of the same trends are observed between the tropane
benzimidazole series (table 1) and the tropane-1,2,4-triazole ser-
ies. Sulfonamides 14a and 14b show that there was not a signifi-
cant difference between endo and exo isomers.
However, carboxamides 14c and 14d do not obey this general
rule. Also noteworthy was that the use of the Maraviroc amine
and acyl motif in analogues 14c and 14d resulted in a significantly
lower potency than that of Maraviroc itself (IC50 HOS = 1.5 nM, IC50
PBL = 2.6 nM). This suggests a substantially different binding mode
of the DAB and Maraviroc scaffolds to CCR5, which may potentially
result in a different resistance profile of compounds in this series
from that of MVC.
Not determined.
Finke and co-workers5 have described the structure–activity
relationship of a series of 4-(piperidin-1-yl)-2-phenyl-1-(phen-
ylsulfonylamino)butane CCR5 antagonists in which only modest
antiviral activity (IC95 P 200 nM) was achieved. It has also been
disclosed that installing a quaternary methyl group at C-2 offers
a considerable improvement in potency (up to IC90 = 3 nM). It
was our hope that this phenomenon could also be observed in
our novel series of tropane-incorporating inhibitors. Table 4 shows
the results for the 2-methyl-2-phenyl DAB series (Scheme 4). A di-
rect comparison of compounds 16a–f with their non- quaternary
counterparts in Tables 1 and 2 shows that the quaternary methyl
group offers little improvement in potency in the HOS assay, with
values generally agreeing within twofold. However, in the case of
examples 7a and 16a, the PBL assay values differ considerably.
The same trends observed in Table 1 are seen in Table 4, with
the N-methylated sulfonamide outperforming non-N-methylated
(16a vs 16b) but having no effect in the carboxamide series (16d
vs 16e).
In general, this series displayed hERG activity (dofetilide bind-
ing assay) which showed a dependence on structural features.
For example, triazoles 14a–f as a class showed less affinity
(IC50 P 10 lM) while the benzimidazoles 7a–i and 11a–c gave
low-micromolar to sub-micromolar IC50s and the 4-piperdine ser-
ies 12a–e gave sub-micromolar IC50s with the exception of 12b.
The pharmacokinetic properties of 7a, 11c, 12f and 16a are
shown in Table 5. While compounds were characterized by a mod-
erate to high clearance, 7a and 12f exhibited low, but measurable
Somewhat inexplicable is the large potency discrepancy be-
tween 3,3-difluorocyclobutyl carboxamide 14e (>20 lM) and 4,4-
difluorocyclohexyl carboxamide 14c (866 nM) despite their similar
size and properties. However, the sulfonamide moiety was again
demonstrated to be superior to the carboxamide.

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M. D. Tallant et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1394–1398
Table 5
of DAB analogues, which were reported to be potent CCR5 binders,
but had only modest antiviral potency in infected cells.5 In addi-
tion, 7a and 12f had moderate clearance value in rat in PK and
low, but measurable bioavailability from oral dosing at 1 mg/kg.
The SAR described herein enables additional explorations towards
improving the antiviral potency and PK in this novel series.
Rat pharmacokinetics for selected analogs at 1 mg/kg IV and POa
Compds
Cl (mL/min/kg)
%F
AUC (ng/mL)
7a
11c
12f
16a
21
62
32
35
5
<1
2
40
0
10
0
<1
a
References and notes
Evaluated in Sprague Dawley rats using 5% mannitol with 0.05% acetic acid as
dose vehicle.
1. Dragic, T.; Litwin, V.; Allaway, G. P.; Martin, S. R.; Huang, Y.; Nagashima, K. A.
K.; Cayanan, C.; Maddon, P. J.; Koup, R. A.; Moore, J. P.; Paxton, W. A. Nature
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2. Kazmierski, W. M.; Gudmundsson, K. S.; Piscitelli, S. C. Annu. Rep. Med. Chem.
2007, 42, 301.
bioavailabilities at this low-dose.10 Metabolite ID experiment on
analog 7b indicate oxidative attack on multiple sites including
the tropane, benzimidazole and 2-phenyl rings, but interestingly
not on the methylene group in SO2–N–CH2-moiety. This would
suggest that the additional methylene group does not pose an
inherent metabolic liability. Furthermore, analog 16a was found
to be moderately permeable in the MDCK cells (Papp = 70 nM/s),
suggesting that the bioavailability is not absorption-limited. Hu-
man and rat hepatocyte data determined that analogs 7a, 11c,
12f and 16a are all rapidly metabolized (t1/2 6 20 min). We thus
believe that oral bioavailability observed in this series is primarily
determined by first-pass metabolism and could potentially be ad-
dressed with further analoging.
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.
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5. (a) Finke, P.; Oates, B.; Mills, S.; MacCoss, M.; Malkowitz, L.; Springer, M.;
Gould, S.; DeMartino, J.; Carella, A.; Carver, G.; Holmes, K.; Danzeisen, R.;
Hazuda, D.; Kessler, J.; Lineberger, J.; Miller, M.; Schleif, W.; Emini, E. Bioorg.
Med. Chem. Lett. 2001, 11, 2475; (b) Caldwell, C. G.; Chen, P.; Finke, P. E.;
Shankaran, K.; Meurer, L. C.; Oates, B.; Dorn, C. P., Jr.; MacCoss, M.; Mills, S. G.;
DeMartino, J. A.; Gould, S. L.; Malkowitz, L.; Siciliano, S. J.; Springer, M. S.;
Braun, J.; Chen, Q.; Hajdu, R.; Kwei, G.; Carella, A.; Carver, G.; Danzeisen, R.;
Hazuda, D. J.; Holmes, K.; Kessler, J.; Lineberger, J.; Miller, M.; Emini, E. A.;
Schleif, W. A. Abstract of Papers, 220th ACS National Meeting, Washington, DC,
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In conclusion, we discovered that in the MDAB series the use of
N-methyl-sulfonamide and endo-tropane motifs leads to very high
level of PBL cellular potency (e.g., for compound 16a). Interestingly,
the use of the same motifs in the DAB series was insufficient to se-
cure high PBL potency (cf. compound 7a). On the other hand, the
use of endo-tropane substituted with the imidazole moiety in 11c
and the bicyclic-pyrrolidine in the DAB series in 12f, again resulted
in high antiviral PBL potency (IC50 = 1 nM). Similar antiviral po-
tency level could not be accomplished in previously described class
6. (a) WO 2004/054974.; (b) Bagley, J.; Riley, T. J. Heterocycl. Chem. 1982, 19, 485.
7. WO 2005/101989. See also Price, D. Synlett 2005, 1133.
8. Woods, G.; Heying, T.; Schwartzman, L.; Grenell, S.; Gasser, W.; Rowe, E.;
Bolgiano, N. J. Org. Chem. 1954, 19, 1290.
9. Muniz-Medina, V.; Jones, S.; Maglich, J.; Galardi, C.; Hollingsworth, R.;
Kazmierski, W.; Ferris, R.; Edelstein, M.; Chiswell, K.; Kenakin, Y. Mol.
Pharmacol. 2009, 75, 490.
10. Maraviroc bioavailability was reported to be 6% at 10 mg/kg PO dose (Drug
Metab. Dispos. 2005, 587–595). However, under conditions employed to
evaluate PK of analogues in Table 5, MVC plasma concentration after oral
dosing was undetectable.