Synthesis and biological evaluation of d-gluconhydroximo-1,5-lactam and its oxime-substituted derivatives as pharmacological chaperones for the treatment of Gaucher disease

Article abstract of DOI:10.1039/c5md00501a

d-Gluconhydroximo-1,5-lactam and its oxime-substituted derivatives were prepared and assessed for inhibition and pharmacological chaperone (PC) activities in Gaucher disease cell lines derived from N370S. The most active compound, O-(d-glucopyranosylidene

Full text of DOI:10.1039/c5md00501a

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RESEARCH ARTICLE
Synthesis and biological evaluation of D-
gluconhydroximo-1,5-lactam and its oxime-
substituted derivatives as pharmacological
chaperones for the treatment of Gaucher
disease†‡
Cite this: DOI: 10.1039/c5md00501a
Jiajia Wang,a Xiaomin Wang,a Yunyan Zhao,a Xiaoyao Ma,a Yue Wan,a
a
a
c
a
b
ab
*
Zhongwei Chen, Hao Chen, Hao Gan, Jing Li, Lei Li, Peng George Wang
a
*
and Wei Zhao
D-Gluconhydroximo-1,5-lactam and its oxime-substituted derivatives were prepared and assessed for inhi-
bition and pharmacological chaperone (PC) activities in Gaucher disease cell lines derived from N370S. The
most active compound, O-(D-glucopyranosylidene) amino-Z-N-dodecylcarbamate (38), gave a nearly 2.0-
fold increase in N370S β-GCase activity at 12.5 μM with no inhibition to other commercially available glu-
cosidases. Docking studies of ligand–enzyme interactions have also been conducted to account for the re-
sults of enzyme activity increase. All these results demonstrate that compound 38 is a promising PC for the
treatment of GD.
Received 2nd November 2015,
Accepted 12th December 2015
DOI: 10.1039/c5md00501a
www.rsc.org/medchemcomm
and known as the non-neuronopathic or adult variant, ac-
counting for more than 90% of all cases. Type 2 and type 3
variants involve central nervous system affections. These prob-
lems are attributed to the deficiency of glucocerebrosidase
(GCase) and ultimately lead to the abnormal accumulation of
GlcCer substrates in lysosomes of GD patients.
Currently, two therapeutic approaches are used for LSDs:
substrate reduction therapy (SRT)5 and enzyme replacement
therapy (ERT).6 SRT drugs, such as NB-DNJ (N-butyl-1-
deoxynojirimycin, Zavesca), aim to inhibit glucosylceramide
synthase (GS) and decrease GlcCer production. However, GS
is indispensable in the process of biosynthetic
glucosylceramide, thus Zavesca was only approved for the
treatment of type 1 GD.7 In contrast, ERT aims to maintain
the levels of GCase activity in patients by supplementing re-
combinant human GCase.8 This therapy approach is also not
suitable for types 2 and 3 GD owing to the disability to cross
the blood–brain barrier.9
1. Introduction
Lysosomal storage disorders (LSDs)1 are usually caused by de-
ficiency of certain lysosomal enzymes, resulting in excessive
storage of corresponding substrates in lysosomes.
Representing the most common LSD, Gaucher disease (GD)2
is caused by recessive mutation in β-glucocerebrosidase
(GCase; EC 3.2.1.45), which is responsible for the hydrolysis
of glucosylceramide to glucose and ceramide in the lyso-
some.3 Although mutant GCase proteins can be synthesized
and functionalized in ER at normal levels, they are not as sta-
ble as the wild-type. Misfolded GCase is easy to accumulate
and degrade due to the efficient quality-control system in the
ER; only correctly folded proteins can be transported to the
Golgi compartment for further maturation. There are mainly
three clinical types of GD disease which differ in the severity
of neurological involvement.4 Type 1 GD is the most common
Recently, pharmacological chaperone therapy (PCT) has
attracted much attention for the treatment of GD and other
LSDs.10 It is assumed that under inhibition concentrations,
small molecules such as competitive inhibitors could specifi-
cally bind to mutant enzymes, assist in folding, then promote
trafficking to lysosomes. Once the inhibitor and mutant-
enzyme complexes get into the lysosome, the acidic and
substrate-rich environment of the lysosome will favor dissoci-
ation and release active enzymes. Liberated mutant enzymes
a State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and
Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin
300071, PR China. E-mail: wzhao@nankai.edu.cn, pwang@nankai.edu.cn;
Fax: +86 22 2350 6290; Tel: +86 22 2350 6290
b The Department of Chemistry, Georgia State University, Atlanta, GA 30302, USA
c Tianjin Chase Sun Pharmaceutical Co. LTD, Tianjin 300071, PR China
† The authors declare no competing interests.
‡ Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5md00501a
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then perform their catalytic function in the lysosome.11 The
dissociated chaperones are either secreted out to the extracel-
lular environment or recycled to interact with other mutant
enzymes to fulfill their functions (Fig. 1).
A large number of iminosugar-type glycomimetics with
GCase PC activity have recently been reported as chaperones,
such as N-nonyl-deoxynojirimycin (NN-DNJ) (1),12 α-1-C-nonyl-
1-deoxynojirimycin (α-1-C-nonyl-DIX) (2),13 isofagomine (IFG)
and its derivatives (3, 4, and 5),14 polyhydroxylated lactam
(6),15 bicyclic isourea (7), guanidines (8)16 and bicyclic
nojirimycin analogues with sp2 iminosugar structures (NOI-
NJ) (9, 10, and 11)17 (Fig. 2). All of these compounds exhibit
high performance as pharmacological chaperones for the
therapy of GD by increasing the cellular GCase catalytic activ-
ity. Previously, we have found that C2-substituted 3,3-
Fig. 2 Chemical structures of pharmacological chaperones for GCase.
dimethyl-N-phenyl-4-amide-1-butyl glucoimidazole showed an 2. Results and discussion
excellent PC activity with a 2.1-fold increase in N370S lym-
2.1 Synthesis
phoblasts at 2.5 μM and a 1.2-fold increase in L444P at 0.5
μM after three-day incubation.18
A successful synthetic strategy toward D-gluconhydroximo-1,5-
lactam derivatives is shown in Scheme 1. Initially, 2,3,4,6-
tetra-O-benzyl-D-glucopyranose-lactam (13) was synthesized
from commercially available methyl-α-D-glucopyranose (12) as
previously reported.21 Treatment of lactam 13 with
Lawesson's reagent afforded the corresponding glucothio-
nolactam (14) in 92% yield.22 Compound 14 was then treated
with hydroxylamine hydrochloride to generate a 10 : 1 mixture
of the hydroximo-lactam (15) and the manno-isomer. The
mixture was separated by flash column chromatography to af-
ford the desired product 2,3,4,6-tetra-O-benzyl-D-gluconhydro-
Hydroximo-lactones (lactone oximes) and the correspond-
ing N-phenylcarbamates are strong and competitive glycosi-
dase inhibitors with the Ki between 10−5 and 10−8 μM.19 In
addition, modification of an oxime with phenyl isocyanate
can dramatically improve its inhibitory ability towards glyco-
sidase. Unprotected aldonhydroximo-lactams are analogues
of aldonolactones; thus related D-gluconhydroximo-1,5-lactam
(GHL) and derivatives may also be potential inhibitors of gly-
cosidases and may be useful for treating other diseases.20 In
this paper, a series of D-gluconhydroximo-1,5-lactam ana-
logues bearing hydrophobic substituents were synthesized
and biologically evaluated as GCase chaperones for GD ther-
apy. We expect that these modified analogues could present
the greatest affinity with mutant GCase at the neutral pH of
ER, resulting in normal folding and formation of a stable
chaperone–enzyme complex followed by trafficking to the ly-
sosome without degradation. Once the mutant enzyme–inhib-
itor complex was in the lysosome, excessive storage of the
substrates in the lysosome promotes the dissociation of the
complex, which can efficiently increase the GCase activity for
the treatment of GD.
Fig. 1 The proposed mechanism of pharmacological chaperones in
treatment of GD and other LSDs.
Scheme 1 Synthesis of the D-gluconhydroximo-1,5-lactam 27 and its
oxime-substituted derivatives 28–38.
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ximo-lactam (15) in a yield of 83%. Compound 15, a key inter-
mediate, was reacted with various isocyanates in the presence
of Et3N to afford the corresponding products. Catalytic
hydrogenolysis (PdIJOH)2/C, H2) for removal of the benzyl pro-
tective groups would break the oxime bond (CN–O bond).
Alternatively, the experiments were carried out with BCl3 in
anhydrous CH2Cl2 at −78 °C for 3 h and then 0 °C for 12 h. A
low temperature was crucial in this step to obtain the ulti-
mate products in high yields (73–85%). The synthesis of the
D-gluconhydroximo-1,5-lactam 27 and its oxime-substituent
derivatives 28–38 is summarized in Table 1. All the synthe-
comparative purposes. The corresponding IC50 values are
listed in Table 2. All synthesized compounds exhibited a poor
inhibition for α/β-galactosidase with the IC50 values above
100 μM, which were selectively against glucosidases.
As shown in Table 2, all synthesized compounds exhibited
comparatively effective inhibition of α and β-glucosidases.
The lack of selectivity may be ascribed to the CN bond of
oxime at C-1. Among analogues bearing an aromatic or a
heterocyclic substitute, 31–35 with IC50 values below 10 μM
showed a slightly stronger inhibitory potency than others for
β-glucosidase. 34 (IC50 = 2.68 μM) showed a 17-fold inhibitory
potency increase compared to 37 for β-glucosidase from
baker's yeast and 29 (IC50 = 3.06 μM) showed a 28-fold inhibi-
tory potency increase compared to 37 for α-glucosidase from
baker's yeast (both except for 38), respectively. Subtle chemi-
cal modifications in the positions of aromatic substituents
for 31–33 and in the size of the aromatic or heterocycle for
34 and 35, which were 4–12-fold more potent than their par-
ent 28, indicate that the presence of heteroatoms in the aro-
matic substituent could slightly improve the binding affinity
for β-glucosidase. In addition, parent 27 and 38 showed weak
or no inhibition for all assayed glycosidases.
1
sized compounds were characterized using H, 13C NMR and
HRMS.
2.2 Glycosidase inhibition
To determine the selectivity profile, synthesized compounds
27–38 were tested as inhibitors against a panel of commer-
cially available glucosidases, including α-glucosidase from
baker's yeast, β-glucosidase from almonds, β-galactosidase
from E. coli, and α-galactosidase from green coffee beans. In-
hibition data for NN-DNJ and IFG were also included for
Table
derivatives
1 D-Gluconhydroximo-1,5-lactam and its oxime-substituted
2.3 Effects of compounds on the activity of GCase and
activity enhancement assays in human N370S lymphoblasts
Isocyanate
Product
Yielda
82%
Most pharmacological chaperones are competitive inhibitors
of their target enzymes. In this study, the chemically synthe-
sized compounds were evaluated as inhibitors of recombi-
nant GCase (imiglucerase, Cerezyme) at pH = 5.2 and pH =
7.0 and the corresponding IC50 values for 27–38 are shown in
Table 3, which showed that the differences in IC50 measured
at pH = 7.0 were not remarkable compared with the values at
pH = 5.2. As controls, inhibition data for NN-DNJ and IFG
were also included which were better pharmacological chap-
erones for mutant GCase. The Ki values tested at pH = 5.2 in-
dicated that parent 27 and analogues 28 and 29 bearing a
phenyl or a naphthyl substituent showed general inhibitory
potency. Subtle chemical modification in the position of aro-
matic substituents with electron-withdrawing groups of fluo-
rine or chloride atom for 31 and 32 or electron-donating
groups of methylthio or thiazole for 33 and 35 did not signifi-
cantly improve the binding affinity. Alkyl substituents such
as tert-butyl substituted 37 showed weak inhibitory potency
with Ki = 30.08 μM, while adamantane substituted 36 showed
slightly higher potency than 37 with Ki = 1.52 μM. Compound
30, bearing a 4-phenoxyphenylcarbamate substituent, was
found to be the strongest inhibitor against imiglucerase and
showed more than 600-fold increased inhibition compared to
37 with Ki = 0.05 μM. This dramatic enhancement of inhibi-
tory potency was partially attributed to the electrostatic inter-
actions involving the π–π stacking of the phenoxyphenyl sub-
stituent with the enzyme. Additionally, both compounds
34 and 38 showed strong inhibition of imiglucerase with
subnanomolar potency (Ki = 0.64 and 0.14 μM, respectively).
76%
78%
81%
84%
85%
74%
81%
73%
83%
85%
a
Yields reported for the removal of benzyl protective groups after
purification on silica gel.
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Table 2 Glycosidase inhibitory activities (IC50) for the synthetic derivative inhibitors against commercial glycosidase
Compd
β-Glucosidase (almond)
α-Glucosidase (baker's yeast)
β-Galactosidase (E. coli)
α-Galactosidase (green coffee beans)
27
28
29
30
31
32
33
34
35
36
37
38
NN-DNJ
IFG
80.3
>100
70.97
3.06
22.02
4.93
18.85
7.03
14.65
7.40
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
31.08
10.70
14.36
7.59
5.82
8.38
2.68
6.21
14.39
45.95
>100
>100
>100
4.09
87.05
>100
>100
>100
Comparative enzyme activity enhancement assays were
conducted in human lymphoblasts derived from Gaucher dis-
ease patients homozygous for N370S mutation. The cells were
incubated with compounds 27–38 or NN-DNJ and IFG at a
range of concentrations from 3.125 to 100 μM for three days
and then lysed. The increase in enzyme activities and the cor-
responding concentrations of compounds are summarized in
Table 3 and Fig. 3. MTT assays were also carried out for in-
tact wild type of CCC-ESF-1 fibroblast cell line at 100 μM, the
highest concentration in activation assays, and no cytotoxicity
was observed (Table S1†).
All synthetic compounds containing various carbamate
modifications displayed at least 1.2-fold GCase activity in-
crease compared to untreated cells, which was attributed to
the inherent hydrophilicity and affinity with GCase. More-
over, even unmodified parent compound 27 can improve the
GCase activity by nearly 1.3-fold in N370S mutant cells. In ad-
dition, NN-DNJ and IFG gave maximal enhancement of 1.41-
and 1.38-fold at 12.5 and 50 μM which are in agreement with
the results previously reported.15,23
The carbamate attached to the aromatic substituents of
28–35 or the presence of oxygen, nitrogen, sulfur or fluoride
atoms in the aromatic substituents of 31–35 reinforces the
hydrogen interaction with the enzyme pocket, which led to a
moderate increase in GCase activity (1.2- to 1.4-fold). Interest-
ingly, though 35 showed an intermediate Ki value, it elicited
a better improvement in GCase activity with a 1.5-fold in-
crease. It is worth noting that compound 38 was an efficient
inhibitor against GCase in vitro and also showed the most
impressive improvement in N370S lymphoblast cells, with a
nearly 2.0-fold increase at 12.5 μM. It can be concluded that both
the hydrophilic aminocyclitol and the long hydrophobic chain
promoted the high affinity with GCase in N370S mutant cells.
As shown in Fig. 3, the concentrations for maximum activ-
ity increase for each compound were varied over the entire
concentration range. Most compounds followed this rule: a
relative GCase activity increase improved with higher concen-
tration, however, thereafter the activity gradually decreased.
Only compound 27 did not reach the peak even at 100 μM.
Table 3 Inhibitory activity against imiglucerase and maximum observed
increase in GCase activity using compounds 27–38 and the positive con-
trols (NN-DNJ and IFG)
Kia
(μM)
IC50 (μM)
GCase activity increaseb
p.N370S
2.4 Molecular docking studies
Compound
pH 5.2
pH 7.0
In order to investigate the chaperone activity, docking studies
were performed using the reported NN-DNJ–GCase complex
(PDB ID: 2V3E) as a template for docking studies. Molecular
operating environment (MOE) was employed to perform the
docking simulation to study the structure–activity relation-
ships of 38, which showed the highest activity, increased by
1.93-fold, among the tested compounds in this work (Fig. 4).
The results in Fig. 4A showed that 38 was positioned at the
center of the binding pocket with an inward-facing conforma-
tion similar to NN-DNJ,24 which places the oxime at the posi-
tion of the anomeric carbon in a native glycoside. The “half
chair form” 1C4 sugar moiety of compound 38 showed the
best docked orientation with the enzyme-active sites, in
which all the hydroxyl moieties in 38 showed hydrogen bond
interactions mainly with important residues N396, W381,
D127, W179, N234 and E235. These interactions seemed to
27
28
29
30
31
32
33
34
35
36
37
38
NN-DNJ
IFG
5.84
12.50
7.21
65.81
19.32
1.43
4.28
11.55
7.94
1.28
1.49
1.47
1.17
1.35
1.32
1.19
1.36
1.23
1.35
1.30
1.93
1.41
1.38
0.32
3.32
0.05
16.82
18.12
9.15
0.84
5.75
1.85
29.06
0.70
1.03
0.74
21.87
23.51
17.19
13.20
12.46
8.37
21.50
5.74
0.79
17.37
12.34
8.12
0.64
6.38
1.52
30.08
0.14
0.62
0.22
1.52
a
The inhibition was competitive in all cases (determined at pH 5.2).
N370S lymphoblasts from Gaucher disease patients were incubated
b
in the presence of each of the compounds for 3 days before enzyme
assay.
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Fig. 3 Increase in GCase activity in N370S lymphoblasts from Gaucher disease patients over a range of concentrations from 100–3.125 μM. The
relative activity in the lysates from treated cells was normalized to the activity in untreated cells. NN-DNJ is N-nonyl-1-deoxynojirimycin and IFG is
isofagomine.
bent conformation and shared the same acid/base catalytic
residue E235 with the endocyclic imino; this extra interaction
between 38 and GCase is the possible reason why 38 is a
more potent inhibitor than NN-DNJ.
In addition, the corresponding interaction in a 2D image
is shown in Fig. 4B. The geometric orientation of 38 was sim-
ilar to the previously observed structure of NN-DNJ with
pGlcCerase. The rigid sp2 iminosugar imposed a certain re-
striction to the oxime substituent; this long aliphatic tail was
oriented toward and well suited to the entrance of the active
site. The docked pose suggested that besides the interactions
of the iminosugar moiety with the active site of
β-glucosidase, the long and linear chains of the substituent
of 38 also established hydrophobic interactions with the resi-
dues Y313, Y244, F347 and W348 (indicated by purple filled
circles).
According to the crystal structure in Fig. 4B, the distances
between loops 1–4 and 38 were greater than IFG24 and bicy-
clic glucoimidazoles18 with each corresponding GCase, which
might explain the result that the Ki values in this work were
not as good as others at the nanomolar level. It was inferred
that just this moderate affinity of compounds with the mu-
tant enzymes assisted the transport of mutant enzymes from
the ER to the lysosome and then they efficiently dissociated
to recover their catalytic activity.
3. Conclusions
In summary, D-gluconhydroximo-1,5-lactam and its oxime-
substituted derivatives have been synthesized and evaluated.
With treating GD related cell line N370S, we found that com-
Fig. 4 Best pose obtained for docking 38 to the GCase structure 2V3E.
(A) Compound 38 bound to the active site of GCase. The side chains of
pound 38, as an efficient pharmacological chaperone for
GCase, could effectively promote the activity of the mutant
protein with a 1.93-fold increase at 12.5 μM; simultaneously,
it has negligible inhibition towards other glycosidases. De-
tailed computational docking studies exhibited that 38 can
stabilize the mutant N370S with high affinity, leading to safe
trafficking to the lysosome. In short, compound 38 with ad-
vantageous enzymatic and cellular properties, deserves fur-
ther study as a potent pharmacological chaperone for the
treatment of Gaucher disease and other LSDs.
the residues involved in binding are shown as sticks; loops 1–4 are
shown in cyan, orange, red and green, respectively; loop 1 (residues
341–350), loop 2 (residues 393–396), loop 3 (residues 312–319), loop 4
(residues 240–246). (B) Corresponding interaction diagrams of 38
against 2V3E that show strong hydrogen bond interactions between
the cyclitol hydroxyl groups and the side chains of residues E235, N234,
E340, D127 and D396. Green lines represent hydrogen bonds.
play an essential role in the binding affinity of ligands. The Z
configuration of 38 facilitated the exocyclic N atom adopt a
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Acknowledgements
10 (a) G. Parenti, EMBO Mol. Med., 2009, 1, 268–279; (b) Y.
Suzuki, S. Ogawa and Y. Sakakibara, Perspect. Med. Chem.,
2009, 3, 7–19.
We thank the National Natural Science Foundation of China
(20332006, 21572105) and the Natural Science Foundation of
Tianjin (12JCYBJC18600) for financial support.
11 (a) E. R. Benjamin, J. J. Flanagan, A. Schilling, H. H. Chang,
L. Agarwal, E. Katz, X. Wu, C. Pine, B. Wustman, R. J.
Desnick, D. J. Lockhart and K. J. Valenzano, J. Inherited
Metab. Dis., 2009, 32, 424–440; (b) R. Khanna, R. Soska, Y.
Lun, J. Feng, M. Frascella, B. Young, N. Brignol, L. Pellegrino,
S. A. Sitaraman, R. J. Desnick, E. R. Benjamin, D. J. Lockhart
and K. J. Valenzano, J. Mol. Ther., 2010, 18, 23–33.
12 A. R. Sawkar, W. C. Cheng, E. Beutler, C. H. Wong, W. E.
Balch and J. W. Kelly, Proc. Natl. Acad. Sci. U. S. A., 2002, 99,
15428–15433.
13 P. Compain, O. R. Martin, C. Boucheron, G. Godin, L. Yu, K.
Ikeda and N. Asano, ChemBioChem, 2006, 7, 1356–1359.
14 R. A. Steet, S. Chung, B. Wustman, A. Powe, H. Do and S. A.
Kornfeld, Proc. Natl. Acad. Sci. U. S. A., 2006, 103,
13813–13818.
15 G.-N. Wang, G. Twigg, T. D. Butters, S. Zhang, L. Zhang, L.-H.
Zhang and X.-S. Ye, Org. Biomol. Chem., 2012, 10, 2923–2927.
16 A. Trapero, I. Alfonso, T. D. Butters and A. Llebaria, J. Am.
Chem. Soc., 2011, 133, 5474–5484.
17 Z. Luan, K. Higaki, M. Aguilar-Moncayo, H. Ninomiya, K.
Ohno, M. I. García-Moreno, C. Ortiz Mellet, J. M. García
Fernandez and Y. Suzuki, ChemBioChem, 2009, 10, 2780–2792.
18 Z. Li, T. Li, S. Dai, X. Xie, X. Ma, W. Zhao, W. Zhang, J. Li
and P. G. Wang, ChemBioChem, 2013, 14, 1239–1247.
19 D. Beer and A. Vasella, Helv. Chim. Acta, 1986, 69, 267–270.
20 (a) G. A. Levvy and S. M. Snaith, Adv. Enzymol. Relat. Areas
Mol. Biol., 1972, 36, 151–181; (b) E. E. Bruchmann, Chem.-
Ztg, 1978, 102, 387–389.
Notes and references
1 (a) M. Jmoudiak and A. H. Futerman, Br. J. Haematol.,
2005, 129, 178–188; (b) A. H. Futerman and G. van Meer,
Nat. Rev. Mol. Cell Biol., 2004, 5, 554–565.
2 J. L. Zeller, A. E. Burke and R. M. Glass, JAMA, 2007, 298.
3 (a) R. O. Brady, Baillieres Clin. Haematol., 1997, 10, 621–634;
(b) B. Winchester, A. Vellodi and E. Young, Biochem. Soc.
Trans., 2000, 28, 150–154.
4 E. Beutler and G. A. Grabowski, Gaucher disease, in the
metabolic and molecular bases of inherited disease, ed. C.
Scriver, A. L. Beaudet, W. S. Sly and D. Valle, McGraw Hill,
New York, 8th edn, 2001, pp. 3635–3668.
5 D. Elstein, C. Hollak, J. M. F. G. Aerts, S. van Weely, M.
Maas, T. M. Cox, R. H. Lachmann, M. Hrebicek, F. M. Platt,
T. D. Butters, R. A. Dwek and A. Zimran, J. Inherited Metab.
Dis., 2004, 27, 757–766.
6 (a) R. O. Brady, Annu. Rev. Med., 2006, 57, 283–296; (b) M.
Rohrbach and J. T. Clarke, Drugs, 2007, 67, 2697–2716.
7 T. Cox, R. Lachmann, C. Hollak, J. Aerts, S. van Weely, M.
Hrebícek, F. Platt, T. Butters, R. Dwek, C. Moyses, I. Gow, D.
Elstein and A. Zimran, Lancet, 2000, 355, 1481–1485.
8 (a) N. W. Barton, R. O. Brady, J. M. Dambrosia, A. M. Di
Bisceglie, S. H. Doppelt, S. C. Hill, H. J. Mankin, G. J.
Murray, R. I. Parker and C. E. Argoff, N. Engl. J. Med.,
1991, 324, 1464–1470; (b) N. J. Weinreb, Expert Opin.
Pharmacother., 2008, 9, 1987–2000; (c) J. M. F. G. Aerts, U.
Yasothan and P. Kirkpatrick, Nat. Rev. Drug Discovery,
2010, 9, 837–838; (d) C. E. Hollak, Core Evidence, 2012, 7,
15–20.
21 T. Li, L. Guo, Y. Zhang, J. Wang, Z. Zhang, J. Li, W. Zhang, J.
Lin, W. Zhao and P. G. Wang, Bioorg. Med. Chem., 2011, 19,
2136–2144.
22 M. K. Tong, G. Papandreou and B. Ganem, J. Am. Chem. Soc.,
1990, 112, 6137–6139.
9 (a) M. Aoki, Y. Takahashi, Y. Miwa, S. Iida, K. Sukegawa, T.
Horai, T. Orii and N. Kondo, Eur. J. Pediatr., 2001, 160,
63–64; (b) C. A. Prows, N. Sanchez, C. Daugherty and G. A.
Grabowski, Am. J. Med. Genet., Part A, 1997, 71, 16–21; (c)
E. H. Davies, A. Erikson, T. Collin-Histed, E. Mengel, A.
Tylki-Szymanska and A. Vellodi, J. Inherited Metab. Dis.,
2007, 30, 935–942; (d) D. Elstein, A. Abrahamov and A.
Zimran, Clin. Genet., 1998, 54, 179–184.
23 (a) E. D. Goddard-Borger, M. B. Tropak, S. Yonekawa, C.
Tysoe, D. J. Mahuran and S. G. Withers, J. Med. Chem.,
2012, 55, 2737–2745; (b) D. D. Jennifer, G. M. Isabel, T.
Gabriele, O. M. Carmen, H. Karsten, D. B. Terry, K. José and
G. G. Sébastien, J. Org. Chem., 2011, 76, 7757–7768.
24 B. Brumshtein, H. M. Greenblatt, T. D. Butters, Y. Shaaltiel,
D. Aviezer, I. Silman, A. H. Futerman and J. L. Sussman,
J. Biol. Chem., 2007, 282, 29052–29058.
Med. Chem. Commun.
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