Design of novel CXCR4 antagonists that are potent inhibitors of T-tropic (X4) HIV-1 replication

Article abstract of DOI:10.1016/j.bmcl.2011.01.021

A novel series of CXCR4 antagonists were identified based on the substantial redesign of AMD070. These compounds possessed potent anti-HIV-1 activity and showed excellent pharmacokinetics in rat and dog.

Full text of DOI:10.1016/j.bmcl.2011.01.021

Bioorganic & Medicinal Chemistry Letters 21 (2011) 1414–1418
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design of novel CXCR4 antagonists that are potent inhibitors of T-tropic (X4)
HIV-1 replication
Renato Skerlj a, , Gary Bridger b, Ernest McEachern b, Curtis Harwig b, Chris Smith b, Alan Kaller b,
⇑
Duane Veale b, Helen Yee b, Krystyna Skupinska b, Rossana Wauthy b, Letian Wang b, Ian Baird b,
Yongbao Zhu b, Kate Burrage b, Wen Yang b, Michael Sartori b, Dana Huskens c, Erik De Clercq 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 CXCR4 antagonists were identified based on the substantial redesign of AMD070. These
compounds possessed potent anti-HIV-1 activity and showed excellent pharmacokinetics in rat and dog.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 2 December 2010
Revised 4 January 2011
Accepted 6 January 2011
Available online 11 January 2011
Keywords:
CXCR4
Chemokine receptor
HIV-1
AMD070
Structure–activity relationship
Recent recommendations of the International AIDS Society
Panel-USA on antiretroviral therapy (ART) for HIV-infected adults
state, that frequent monitoring of patient HIV-1 RNA is necessary
to identify and manage treatment failure, with the goal being
suppression of HIV-1 RNA below quantification limits.1 Frequent
monitoring is necessary to identify virologic failure due to the
emergence of resistance variants. Recently approved drugs with
novel mechanisms of action such as raltegravir2 and mariviroc3
that target HIV integrase and the chemokine receptor CCR5 add
to the armory of drugs available to treat HIV and provide additional
treatment options for managing resistance.
The discovery of the chemokine receptors CXCR4 and CCR5 in
1996 as co-receptors for HIV for cell entry by HIV-14 prompted a
concerted research effort to discover novel antagonists of these
receptors. Our longstanding research interest in CXCR4 led to the
first clinical proof of concept that blocking CXCR4 with a small
molecule antagonist, AMD3100, results in viral load reduction in
T-tropic (X4) HIV-1 infected patients.5 This was followed by the
discovery and development of the first orally bioavailable CXCR4
antagonist AMD0706 that also demonstrated viral load reduction
in T-tropic (X4) HIV-1 infected patients.7 In addition to HIV, CXCR4
and its specific ligand, CXCL12 [stromal cell derived factor-1
(SDF-1)], have been implicated to play a role in tumor progression,
angiogenesis, metastasis and survival.8 Moreover, the CXCR4/
CXCL12 axis also plays an important role in the homing and reten-
tion of progenitor cells in the bone marrow microenvironment.9
Consequently, based on compelling clinical data, plerixafor
(AMD3100) was approved in the US in 2008 for mobilization of
hematopoietic stem cells in patients with non-Hodgkins’s
lymphoma (NHL)10 and multiple myeloma (MM).11
Recently we reported on our medicinal chemistry efforts that
led to the design and synthesis of oral agents such as AMD0706
as well as novel heterocyclic analogs of AMD070.12 In addition
researchers from GlaxoSmithKline have reported on an extensive
analog program of AMD070.13 In this Letter, we disclose our efforts
on modifying AMD070 (1) by sequentially replacing the benzimid-
azole ring with a substituted pyridine ring (2), opening up the
tetrahydroquinoline ring (3), and combining both of these modifi-
cations to afford the open chain analogs (4) while still maintaining
potent HIV-1 inhibition (Fig. 1).
The primary data used to drive the SAR were the ability of these
compounds to inhibit replication of HIV-1 NL4.3, using exclusively
CXCR4 for viral entry into its target cells. In addition, the ability of
these compounds to specifically interact with CXCR4 were also
⇑
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.2011.01.021

R. Skerlj et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1414–1418
1415
the effect on antiviral potency examined (Table 1). Gratifyingly
the unsubstituted pyridine analog 2a was threefold less potent
when compared to 1; IC50 of 15.5 versus 4.8 nM.6 Walking a methyl
group around the pyridine ring demonstrated the following trend
regarding potency: 6-Me (2e) > 5-Me (2d) > 3-Me (2b) > 4-Me
(2c), for example, compound 2e was twofold more potent than 1
with an IC50 of 2.9 nM whereas 2d had comparable potency (IC50
of 5.3 nM). Interestingly the 3,5-dimethyl analog 2g resulted in
an eightfold enhancement in potency compared to the 5-methyl
analog 2d (IC50 of 0.63 vs 5.3 nM). Although the 6-methyl analog
2e was the most potent of the methyl series, substitution at the
6-position with either an H-bond donor (amino 2h) or H-bond
acceptor (methoxymethyl 2i) moiety resulted in a 10- and 191-fold
drop in potency relative to 2e. On the other hand, substitution at
the 3-position appears to be well tolerated (2b, 2j–n). Apart from
the hydroxyl group 2j other substituents were either equipotent
(amino 2k) or enhanced potency; the bulky iPr group 2l is approx-
imately threefold more potent than 2b and the hydroxymethyl 2m
and chloro 2n were 11- and 78-fold more potent than 2b.
The synthetic strategy used to prepare compounds 2 is similar
to methodology previously reported.12 The key step in many of
these examples was the generation of the appropriately function-
alized bromomethyl (2j–k) or aldehyde moiety (2a–i, 2l–n) of
the pyridine ring which was then coupled with 2-(4-((5,6,7,8-
tetrahydroquinolin-8-yl)amino)butyl)isoindoline-1,3-dione18 5 via
N-alkylation or reductive amination (Scheme 1). The key interme-
diate 5 was synthesized by phthalamide protection of commer-
cially available 4-aminobutan-1-ol followed by TPAP oxidation to
the aldehyde and subsequent reductive amination with 8-amino-
5,6,7,8-tetrahydroquinoline.19 The phthalamide group was easily
deprotected using an excess of hydrazine in ethanol at room tem-
perature followed by salting with HBr in acetic acid to afford the
final compounds as hydrobromide salts.
N
N
N
R
R1
W
Me
R
N
N
N
N
N
N
2
W
R
W
NH
R1
W
N
4
N
1
N
NH
W= (CH2)4NH2
3
Figure 1. Structure of racemic AMD070 (1) and related analogs 2, 3 and 4.
measured by the effects on SDF-1 induced Ca2+ flux in CD4+CXCR4+T
cells (CEM-CCRF) cells and were found to correlate with the anti-
HIV-1activity(Tables1and3). Althoughthemoleculescontainaste-
reocenter the SAR was based on the racemic mixture.
Based on our early pharmacophore model,14 where it was deter-
mined that the optimal spacer between the tertiary nitrogen atom
and the adjoining nitrogen was a two carbon linker, we chose to re-
place the benzimidazole ring with a substituted pyridine ring spe-
cifically attached at the 2-position (Table 1). In contemplating
redesigns to compound 1 we were cognizant of the importance
of maintaining a basic amine moiety based on receptor mutagene-
sis studies showing the dependence on aspartic acid residues Asp
171 and Asp 262 as well as other amino acid residues on the bind-
ing affinity for compounds AMD310015 and AMD070.16 The impor-
tance of aspartic acid residues was recently corroborated by the
first X-ray crystal structure of ligands bound to CXCR4.17 Conse-
quently a series of 2-substituted pyridines were synthesized and
Having determined that a substituted pyridine ring in the place
of the benzimidazole ring resulted in compounds with enhanced
anti-HIV-1 activity (Table 1) we shifted our attention to gauge
Table 1
Anti-HIV-1 activity, cytotoxicity and calcium signaling (SDF-1) inhibition of compounds 2a,b
N
N
NH2
3
N
R
6
4
5
Ca2+ Flux IC50 (nM)
c
d
e
Compound
R
HIV-1 IC50 (nM)
CC50 (nM)
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
H
3-Me
4-Me
5-Me
15.3 (n = 1)
23.3 (n = 2)
47.8 (n = 1)
5.3 (n = 1)
2.9 (n = 3)
17 (n = 2)
164,900
32,400
36,900
74 (n = 3)
18 (n = 4)
91 (n = 2)
35 (n = 2)
53 (n = 5)
38 (n = 3)
19 (n = 4)
49 (n = 1)
1621 (n = 1)
129 (n = 3)
27 (n = 4)
63 (n = 4)
79 (n = 2)
44 (n = 3)
35,300
6-Me
298,700
149,400
32,600
157,900
>153,500
148,800
168,800
33,800
4,6-diMe
3,5-diMe
6-NH2
6-CH2OMe
3-OH
3-NH2
3-iPr
3-CH2OH
3-Cl
0.63 (n = 3)
30 (n = 2)
553 (n = 1)
113 (n = 2)
19.7 (n = 3)
8.4 (n = 1)
2.1 (n = 1)
0.4 (n = 1)
154,800
190,900
a
b
c
Assay conditions reported in Ref. 6.
Assays were performed in duplicate and values represent the mean with standard deviations <30% of the mean. Bracketed values represent the number of experiments.
CD4+CXCR4+ lymphocytic MT-4 cell line were infected with the X4 HIV-1 NL4.3 strain. IC50 is the concentration of the compound required to protect 50% of the cells
against viral cytopathicity.
d
CC50 is the concentration required to reduce the viability of MT-4 cells by 50%.
e
CEM-CCRF (CD4+CXCR4+) T cell line. IC50 is the concentration of the compound required to inhibit 50% of the SDF-1-induced Ca2+ signaling.

1416
R. Skerlj et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1414–1418
Compounds 3 were prepared either starting from an appropri-
NH2
OH
ately functionalized aldehyde (3a–b, 3d, 3f–l) or primary amine
(3c, 3e, 3m) as exemplified by the preparation of 3k and 3e (Scheme
2). For example, in the synthesis of 3k commercially available
1-(5-methylpyridin-2-yl)ethanone was coupled with tert-butyl
(4-aminobutyl)carbamate (prepared by the selective Boc protection
of butane 1,4-diamine) in the presence of NaBH(OAc)3 to afford the
secondary amine 6. N-alkylation with N-Boc-chloromethylbenzimi-
dazole6 in the presence of Hunig’s base and KI followed by concom-
itant Boc deprotection and saltingwith HBr in acetic acid afforded 3k
as the hydrobromide salt. In the case of 3e commercially available
2-(pyridin-2-yl)propane-2-amine underwent reductive amination
with4-(1,3-dioxoisoindolin-2-yl)butanal (preparedby phthalamide
protection of the amino alcohol followed by oxidation to the
aldehyde) to afford the secondary amine 7 which then underwent
N-alkylation with N-Boc-chloromethylbenzimidazole6 as described
above. Deprotection of the phthalamide group with hydrazine in
ethanol followed by treatment with HBr in acetic acid afforded 3e
as the hydrobromide salt (Scheme 2). Compounds 4 were synthe-
sized using similar methodology.
By demonstrating that compound 1 could be substantially rede-
signed by first replacing the benzimidazole ring with a substituted
pyridine ring and secondly opening up the tetrahydroquinoline
ring to a pyridinyl ethanamine while still maintaining potent
anti-HIV-1 activity, a series of analogs 4 were synthesized where
both of these changes were incorporated (Table 3). We were
pleased to find that these compounds had comparable potency to
the precursors 2 and 3 verifying our original pharmacophore
hypothesis.14 The SAR in general tracked what was observed for
compounds 2. For example, the IC50 of the 3,5-dimethyl analog
2g was 0.63 versus 1.8 nM for the 3,5-dimethyl analog 4g. The
IC50 of the 6-Me analog 2e was 2.9 versus 15.1 nM for the 6-Me
analog 4f. However, the 3-Me analog 4a was 21-fold more potent
than the corresponding analog 2b, IC50 of 23.3 versus 1.1 nM. Inter-
estingly, the analog 4h with a 4-Me group on the northern pyridine
ring had comparable activity to 4a, 0.3 versus 1.1 nM.
a-c
d-f
N
O
2j-k
HN
N
5
g,
O
e-f
2a-i, 2l-n
Scheme 1. Reagents: (a) Phthalic anhydride, CHCl3, 70 °C; (b) TPAP, NMO, CH2Cl2;
(c) 8-amino-5,6,7,8-tetrahydroquinoline, NaBH(OAc)3, CH2Cl2; (d) RX, KI, DIPEA,
CH3CN, reflux; (e) N2H4, EtOH; (f) HBr, AcOH; (g) RCHO, NaBH(OAc)3, CH2Cl2.
the effects of opening up the tetrahydroquinoline ring of 1
(Table 2). Surprisingly a dramatic effect on anti-HIV-1 potency
was observed as the steric bulk at the benzylic position (R1) was in-
creased. For instance, the closest analog to 1, compound 3a where
R1 is a methyl group was approximately fourfold less active com-
pared to 1 with an IC50 of 18 nM. However, the ethyl analog 3b
was 182-fold less potent and the more sterically demanding
isopropyl analog 3c was 4000-fold less potent. A similar loss in
potency was also observed for the phenyl analog 3d and the gem
dimethyl analog 3e indicating the sensitivity to steric bulk at this
position perhaps due to the binding orientation to CXCR4. Interest-
ingly, when R1 was a hydrogen atom 3f moderate potency was ob-
served, IC50 of 410 nM. To further probe the SAR the addition of an
H-bond donor hydroxyl group at the 3-position 3g of the pyridine
ring resulted in the complete abolition of activity. However, if the
isopropyl group was substituted at the 3-position 3h rather than
the benzylic position comparable potency to the unsubstituted
analog 3f was observed suggesting that sterically demanding
groups were tolerated at the 3-position. The pyridine ring was also
found to be sensitive to substitution since the walking of a methyl
group (3i–l) around the pyridine ring of 3a resulted in a 24- to 230-
fold loss in activity other than the 5-Me analog 3k which was
approximately fivefold more potent than 3a, for example, IC50 of
3.8 versus 18 nM (Table 2).
Several of the more potent compounds with acceptable ADME
properties were chosen for further evaluation as anti-viral agents
(Table 4). Since we had previously shown that the (S)-enantiomer
of AMD0706 and related compounds had a marked increase in anti-
HIV-1 potency relative to the racemates these compounds were
synthesized as the hydrochloride salts of the (S)-enantiomer.20 In
general this observation was corroborated although the potency
enhancement was not as pronounced as previously observed, for
example, the IC50 of (S)-2e, 2k, 3a and 4a were 2.4, 7.7, 1.6, 1.4
and 1.1 nM, respectively, a 1-, 12-, 13- and 6-fold increase (Tables
1–4). However, we were pleased to find that the IC50 for X4 HIV-1
infection in PBMC’s was comparable to that of the MT-4 CD4+T cell
line for all compounds with a range of 2.0–15.8 nM. In addition,
evidence that these compounds are antagonists of CXCR4 was pro-
vided by the competitive binding with 125I-SDF-1 in CD4+CXCR4+ T
Table 2
Anti-HIV-1 activity and cytotoxicity of compounds 3a
4
R
5
3
R1
6
N
N
N
NH2
HN
Compound
R
R1
HIV-1 IC50 (nM)
CC50 (nM)
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
H
H
H
H
H
3-OH
3-iPr
3-Me
4-Me
5-Me
6-Me
6-NH2
Me
Et
iPr
Ph
Me2
H
18 (n = 2)
>160,900
>161,800
>161,900
>148,300
>159,300
151,100
a
b-c
874 (n = 1)
16300 (n = 1)
13300 (n = 1)
2500 (n = 1)
41 (n = 1)
>149200 (n = 1)
34 (n = 2)
505 (n = 3)
438 (n = 2)
3.8 (n = 1)
3k
N
N
HN
O
NH
6
Boc
d
H
H
>149,200
145,100
b, e, c
N
N
O
3e
NH2
HN
Me
Me
Me
Me
Me
>146,100
>141,600
>146,200
>167,200
>149,400
N
7
3j
3k
3l
O
4100 (n = 1)
2290 (n = 1)
Scheme 2. Reagents: (a) NH2(CH2)4NHBoc, NaBH(OAc)3, CH2Cl2; (b) N-Boc-2-
chloromethylbenzimidazole, KI, DIPEA, CH3CN, reflux; (c) HBr, AcOH; (d) 4-(1,3-
dioxoisoindolin-2-yl)butanal, NaBH(OAc)3, CH2Cl2; (e) N2H4, EtOH.
3m
a
See footnotes in Table 1.

R. Skerlj et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1414–1418
1417
Table 3
Anti-HIV-1 activity, cytotoxicity and calcium signaling (SDF-1) inhibition of compounds 4a
4
R
5
3
R1
6
N
N
N
NH2
HN
Compound
R
R1
HIV-1 IC50 (nM)
CC50 (nM)
Ca2+ flux IC50 (nM)
4a
4b
4c
4d
4e
4f
3-Me
H
H
H
H
H
H
H
4-Me
1.1 (n = 2)
18.4 (n = 1)
39.1 (n = 2)
1.6 (n = 2)
48.1 (n = 1)
15.0 (n = 1)
1.8 (n = 2)
0.3 (n = 2)
45,400
23 (n = 6)
72 (n = 2)
111 (n = 1)
18 (n = 2)
66 (n = 1)
183 (n = 2)
20 (n = 2)
8 (n = 2)
3-NH2
3-CF3
3-iBu
5-Me
6-Me
167,200
>155,400
157,500
158,300
>145,400
163,100
138,236
4g
4h
3,5-diMe
3-Me
a
See footnotes in Table 1.
Table 4
Anti-HIV-1 activity, fold protein shift and SDF-1 binding inhibition of compounds (S)-2e, 2g, 2k, 3a and 4aa
Compound
HIV-1 MT-4
IC50 (nM)
HIV-1 PBMC
IC50 (nM)
Fold IC50
125I-SDF-1 binding
IC50 (nM)
protein shiftc
a
a,b
d
(S)-2e
(S)-2g
(S)-2k
(S)-3a
(S)-4a
2.4 (n = 4)
7.7 (n = 3)
1.6 (n = 3)
1.4 (n = 4)
1.1 (n = 1)
15.8
3.6
2.1
2.0
2.1
0.6
2.8
4.3
5.4
14.2
96.1
62.9
10.9
16.6
35.8
a
b
c
Assays were performed in triplicate and values represent the mean with standard deviations <30% of the mean. Bracketed values represent the number of experiments.
Peripheral blood mononuclear cells (PBMC) were isolated from healthy volunteers and infected by X4 HIV-1 as reported in Ref. 6.
Fold IC50 protein shift is the shift in the X4 HIV-1 PBMC antiviral assay in the presence of 1 mg/ml of
a-acid glycoprotein.
d
Competitive binding studies against CXCR4 were performed in human CD4+CXCR4+ CEM-CCRF cells as reported in Ref. 6.
Table 5
Pharmacokinetics of (S)-2e, 2g, 2k, 3a and 4a in rat and doga
Compound
Species
Rat
Cmax
(lM)
AUC0-inf (h
lM)
CL (ml/min/kg)
V (L/kg)
T1/2 (h)
F (%)
(S)-2e
(S)-2g
(S)-2k
(S)-3a
(S)-4a
(S)-2e
(S)-2g
(S)-2k
(S)-3a
(S)-4a
1.46
2.70
1.66
0.18
1.58
2.06
7.16
7.74
1.33
1.38
8.75
20.7
8.73
0.33
11.19
7.75
22.06
21.20
1.7
163.3
31.7
83.3
113.3
98.3
11.3
3.3
5.0
25
11.7
39.8
28.5
24.1
16.6
36.9
2.1
8.7
9.6
8.5
13.8
2.8
10.5
3.4
1.7
4.4
2.1
39.6
19
87
42
44
2
67
45
51
84
20
56
Dog
3.1
13
7.49
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
cells with the IC50 ranging from 11 to 96 nM (Table 4). Finally, the
anti-viral activity of these compounds was assessed in the pres-
ence of 1 mg/mL of a-acid glycoprotein (AGP) and we were pleased
to observe that the shift in activity was moderate ranging from
0.6- to 5.4-fold (Table 4).
Based on the moderate fold protein shift and the excellent
potency these compounds were profiled in rat and dog pharmaco-
kinetics (Table 5). In general these compounds showed moderate
to excellent exposure and oral bioavailability other than (S)-3a
which was rapidly cleared in both rat and dog resulting in low oral
bioavailability. For example, the 3,5-dimethyl analog (S)-2g
showed low clearance and long half life with a corresponding dura-
ble exposure and good oral bioavailability in both rat and dog. This
was similarly observed for (S)-2e, 2k and 4a.
In summary we identified a novel series of small molecule
antagonists based on the redesign of AMD070. These molecules
are antagonists of the chemokine receptor CXCR4 based on inhibi-
tion of SDF-1 induced calcium signaling and 125I-SDF-1 binding and
are potent inhibitors of HIV-1 replication. Based on encouraging
ADME data and pharmacokinetic data these compounds were fur-
ther advanced to rodent toxicology studies.
Supplementary data
Supplementary data (characterization data for compounds
2a–b, 2d–e, 2g–h, 2k–n, 3a, 3e, 3j–k, 4a, 4d, 4g–h, 6, 7) associated
with this article can be found, in the online version, at doi:10.1016/
j.bmcl.2011.01.021.

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R. Skerlj et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1414–1418
11. Dipersio, J. F.; Stadtmauer, E. A.; Nademanee, A.; Micallef, I. N.; Stiff, P. J.;
References and notes
Kaufman, J. L.; Maziarz, R. T.; Hosing, C.; Fruehauf, S.; Horwitz, M.; Cooper, D.;
Bridger, G.; Calandra, G. Blood 2009, 113, 5720.
12. Skerlj, R.; Bridger, G.; McEachern, E.; Harwig, C.; Smith, C.; Wilson, T.; Veale, D.;
Yee, H.; Crawford, J.; Skupinska, K.; Wauthy, R.; Yang, W.; Zhu, Y.; Bogucki, D.;
Di Fluri, M.; Langille, J.; Huskens, D.; De Clercq, E.; Schols, D. Bioorg. Med. Chem.
Lett. 2011, 21, 262.
1. Thompson, M. A.; Aberg, J. A.; Cahn, P.; Montaner, J. S. G.; Rizzardini, G.; Telenti,
A.; Gatell, J. M.; Gunthard, H. F.; Hammer, S. M.; Hirsch, M. S.; Jacobsen, D. M.;
Reiss, P.; Richman, D. D.; Volberding, P. A.; Yeni, P.; Schooley, R. T. JAMA 2010,
304, 321.
2. Steigbeigeel, R. T.; Cooper, D. A.; Kumar, P. N.; Eron, J. E.; Schechter, M.;
Markowitz, M.; Loufty, M. R.; Lennox, J. L.; Gatell, J. M.; Rockstroh, J. K.;
Katlama, C.; Yeni, P.; Lazzarin, A.; Clotet, B.; Zhao, J.; Chen, J.; Ryan, D. M.;
Rhodes, R.; Killar, J. A.; Gilde, L. R.; Strohmaier, K. M.; Meibohm, A. R.; Miller, M.
D.; Hazuda, D. J.; Nessly, M. L.; DiNubile, M. J.; Isaccs, R. D.; Nguyen, B.-Y.;
Teppler, H. N. Eng. J. Med. 2008, 359, 339.
3. Gulick, R. M.; Lalezari, J.; Goodrich, J.; Clumeck, N.; DeJesus, E.; Horban, A.;
Nadler, J.; Clotet, B.; Karlsson, A.; Wohlfeiler, M.; Montana, J. B.; McHale, M.;
Sullivan, J.; Ridgway, C.; Felstead, S.; Dunne, M. W.; van der Ryst, E.; Mayer, H.
N. Eng. J. Med. 2008, 359, 1429.
4. (a) Feng, Y.; Broder, C. C.; Kennedy, P. E.; Berger, E. A. Science 1996, 272, 872; (b)
Trkola, A.; Dragic, T.; Arthos, J.; Binley, J. M.; Olson, W. C.; Allaway, G. P.; Cheng-
Mayer, C.; Robinson, J.; Maddon, P. J.; Moore, J. P. Nature 1996, 384, 184.
5. (a) Hendrix, C. W.; Collier, A. C.; Lederman, M. M.; Schols, D.; Pollard, R. B.;
Brown, S.; Jackson, J. B.; Coombs, R. W.; Glesby, M. J.; Flexner, C. W.; Bridger, G.
J.; Badel, K.; MacFarland, R. T.; Henson, G. W.; Calandra, G. J. Acquir. Immune
Defic. Syndr. 2004, 37, 1253; (b) Franzen, S.; Bridger, G.; Whitcomb, J. M.; Toma,
L.; Stawiski, E.; Parkin, N.; Petropoulos, C. J.; Huang, W. Antimicrob. Agents
Chemother. 2008, 52, 2608.
13. (a) Gudmundsson, K. S.; Sebahar, P. R.; Richardson, L. D.; Miller, J. F.; Turner, E.
M.; Catalano, J. G.; Spaltenstein, A.; Lawrence, W.; Thomson, M.; Jenkinson, S.
Bioorg. Med. Chem. Lett. 2009, 19, 5048; (b) Gudmundsson, K. S.; Boggs, S. D.;
Catalano, J. G.; Svolto, A.; Spaltenstein, A.; Thomson, M.; Wheelan, P.;
Jenkinson, S. Bioorg. Med. Chem. Lett. 2009, 19, 6399; (c) Miller, J. F.; Turner,
E. M.; Gudmundsson, K. S.; Jenkinson, S.; Splatenstein, A.; Thomson, M.;
Wheelan, P. Bioorg. Med. Chem. Lett. 2010, 20, 2125; (d) Catalano, J. G.;
Gudmundsson, K. S.; Svolto, A.; Boggs, S. D.; Miller, J. F.; Spaltenstein, A.;
Thomson, M.; Wheelan, P.; Minick, D. J.; Phelps, D. E.; Jenkinson, S. Bioorg. Med.
Chem. Lett. 2010, 20, 2186; (e) Miller, J. F.; Gudmundsson, K. S.; Richardson, L.
D.; Jenkinson, S.; Spaltenstein, A.; Thomson, M.; Wheelan, P. Bioorg. Med. Chem.
Lett. 2010, 20, 3026.
14. Bridger, G. J.; Skerlj, R. T.; Hernandez-Abad, P. E.; Bogucki, D. E.; Wang, Z.; Zhou,
Y.; Nan, S.; Boehringer, E. M.; Wilson, T.; Crawford, J.; Metz, M.; Hatse, S.;
Princen, K.; De Clercq, E.; Schols, D. J. Med. Chem. 2010, 53, 1250.
15. Gerlach, L. O.; Skerlj, R. T.; Bridger, G. J.; Schwartz, T. W. J. Biol. Chem. 2001, 276,
14153.
16. Wong, R. S.; Bodart, V.; Metz, M.; Labrecque, J.; Bridger, G.; Fricker, S. P. Mol.
Pharmacol. 2008, 74, 1485.
17. Wu, B.; Chien, E. Y. T.; Mol, C. D.; Fenalti, G.; Liu, W.; Katritch, V.; Abagyan, R.;
Brooun, A.; Wells, P.; Bi, F. C.; Hamel, D. J.; Kuhn, P.; Handel, T. A.; Cherezov, V.;
Stevens, R. C. Science 2010, 330, 1066.
18. Crawford, J. B.; Chen, G.; Gauthier, D.; Skerlj, R.; Baird, I. R.; Wilson, T. R. U.S.
Patent Application 11/077,896, 2005.
19. Skupinska, K. A.; McEachern, E. J.; Skerlj, R. T.; Bridger, G. J. J. Org. Chem. 2002,
67, 7890.
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.;
Princen, K.; De Clercq, E.; Schols, D. J. Med. Chem. 2010, 53, 3376.
7. Moyle, G.; DeJesus, E.; Boffito, M.; Wong, R. S.; Gibney, C.; Badel, K.; MacFarland,
R.; Calandra, G.; Bridger, G.; Becker, S. Clin. Infect. Dis. 2009, 48, 798.
8. Teicher, B. A.; Fricker, S. P. Clin. Cancer Res. 2010, 16, 2927.
9. Ma, Q.; Jones, D.; Springer, T. A. Immunity 1999, 10, 463.
10. DiPersio, J. F.; Micallef, I. N.; Stiff, P. J.; Bolwell, B. J.; Maziarz, R. T.; Jacobsen, E.;
Nademanee, A.; McCarty, J.; Bridger, G.; Calandra, G. J. Clin. Oncol. 2009, 27,
4767.
20. Skupinska, K. A.; McEachern, E. J.; Baird, I. R.; Skerlj, R. T.; Bridger, G. J. J. Org.
Chem. 2003, 68, 3546.