N-Guanidino Derivatives of 1,5-Dideoxy-1,5-imino-d-xylitol are Potent, Selective, and Stable Inhibitors of β-Glucocerebrosidase

Article abstract of DOI:10.1002/cmdc.201700050

A series of lipidated guanidino and urea derivatives of 1,5-dideoxy-1,5-imino-d-xylitol were prepared from d-xylose using a concise synthetic protocol. Inhibition assays with a panel of glycosidases revealed that the guanidino analogues display potent inhibition against human recombinant β-glucocerebrosidase with IC₅₀ values in the low nanomolar range. Related urea analogues of 1,5-dideoxy-1,5-imino-d-xylitol were also synthesized and evaluated in the same fashion and found to be selective for β-galactosidase from bovine liver. No inhibition of human recombinant β-glucocerebrosidase was observed for the urea analogues. Computational studies provided insight into the potent activity of analogues bearing the substituted guanidine moiety in the inhibition of lysosomal glucocerebrosidase (GBA).

Full text of DOI:10.1002/cmdc.201700050

DOI: 10.1002/cmdc.201700050
Communications
N-Guanidino Derivatives of 1,5-Dideoxy-1,5-imino-d-xylitol
are Potent, Selective, and Stable Inhibitors of
b-Glucocerebrosidase
ˇ
ˇ
ˇ
ˇ
Alen Sevsek, Luka Srot, Jakob Rihter, Masa Celan, Linda Quarles van Ufford, Ed E. Moret,
Nathaniel I. Martin,* and Roland J. Pieters*[a]
A series of lipidated guanidino and urea derivatives of 1,5-di-
deoxy-1,5-imino-d-xylitol were prepared from d-xylose using
a concise synthetic protocol. Inhibition assays with a panel of
glycosidases revealed that the guanidino analogues display
potent inhibition against human recombinant b-glucocerebro-
sidase with IC50 values in the low nanomolar range. Related
urea analogues of 1,5-dideoxy-1,5-imino-d-xylitol were also
synthesized and evaluated in the same fashion and found to
be selective for b-galactosidase from bovine liver. No inhibition
of human recombinant b-glucocerebrosidase was observed for
the urea analogues. Computational studies provided insight
into the potent activity of analogues bearing the substituted
guanidine moiety in the inhibition of lysosomal glucocerebrosi-
dase (GBA).
natural relative isofagomine (IFG, 6), are of particular inter-
est[14,15] and a number of syntheses of these compounds have
been reported.[16–18] It has also been demonstrated that syn-
thetically modified N-substituted iminosugars often possess
improved specificities and potent inhibition toward glycosidas-
es.[19–21] In this context, some N-alkylated iminosugars, such as
2, 3, 5, 7, 8 and 9, have already shown promise as potent gly-
cosidase inhibitors.[22–32] Our research group’s activities in this
area have focused on preparing iminosugar analogues with an
sp2 hybridized endocyclic nitrogen.[33] In doing so both the
conformation and charge delocalization of the endocyclic ni-
trogen atom is altered. These modifications have resulted in in-
teresting specificity changes in comparison with the parent
iminosugars.[34] To this end, we recently attempted the synthe-
sis of a series of lipidated DNJ guanidine analogues (com-
pounds I, Scheme 1).[35] Interestingly, we found that such N-al-
kylated guanidine DNJ analogues I spontaneously cyclized to
generate the corresponding stable bicyclic isoureas II. Gratify-
ingly, the isoureas proved to be very potent and specific inhibi-
tors of b-glucocerebrosidase.[35]
Creating potent and selective glycosidase inhibitors is an im-
portant goal in medicinal chemistry[1] due to their therapeutic
potential in the treatment of a variety of carbohydrate-mediat-
ed diseases.[2–12] In this respect, iminosugars are privileged lead
compounds because of their complementarity to glycosidase
active sites and aspects of the relevant transition states in the
hydrolysis processes catalyzed by glycosidases.[13] Glycomimet-
ics that comprise an endocyclic nitrogen, such as the naturally
occurring 1-deoxynojirimycin (DNJ, 1, Figure 1) as well as 1,5-
dideoxy-1,5-imino-d-xylitol (DIX, 4) and their closely related un-
Our previous studies established that formation of the cyclic
isourea II proceeds via the guanidine species, which is prone
to cyclization by action of the 6-OH group. We here report
a strategy designed to circumvent this process wherein N-sub-
stituted guanidine analogues of DIX (4), lacking the 6-OH
group of DNJ, were prepared and found to be stable. Previous
reports indicate that a DIX analogue bearing an unsubstituted
guanidinium moiety (10) displays a 100-fold enhancement in
the inhibition of almond b-glycosidase (Figure 2).[36] However,
N-guanidino-alkylated variants of DIX (A) have not been stud-
ied. We here report the synthesis and testing of new guanidini-
um compounds of type A as well as the corresponding urea
derivatives B (Figure 2) both derived from DIX and lacking the
hydroxymethyl found in DNJ that causes the cyclization. Inter-
estingly, it has also been shown that the hydroxymethyl of
DNJ can have a detrimental effect on its GBA binding when
compared with unsubstituted DIX.[32]
Figure 1. Chemical structures of selected iminosugar-based glycosidase in-
hibitors.
ˇ
ˇ
ˇ
[a] A. Sevsek, L. Srot, J. Rihter, M. Celan, L. Q. van Ufford, Dr. E. E. Moret,
Dr. N. I. Martin, Prof. Dr. R. J. Pieters
Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P.O. Box
3508 TB, 3508 TB Utrecht (The Netherlands)
E-mail: r.j.pieters@uu.nl
n.i.martin@uu.nl
Supporting information (detailed experimental procedures with full char-
acterization of all new compounds) and the ORCID identification num-
ber(s) for the author(s) of this article can be found under:
http://dx.doi.org/10.1002/cmdc.201700050.
Figure 2. Unsubstituted guanidinium DIX derivative 10[36] and general struc-
tures of A guanidine and B urea DIX derivatives prepared in this work.
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Scheme 1. Previously published spontaneous cyclization of guanidine (I) compounds to bicyclic isoureas (II) derived from DNJ precursor.[35]
Scheme 2. Synthetic route used to prepare 1,5-dideoxy-1,5-imino-d-xylitol derivatives with NG-substituted A) guanidine and B) urea analogues.
The synthetic strategy used in preparing the guanidinium
and urea analogues of DIX (4), is outlined in Scheme 2. Benzyl
protected 1,5-dideoxy-1,5-imino-d-xylitol 11 was synthesized
according to the literature procedure[37] and used as a starting
material for the preparation of both the guanidine and urea
analogues. As indicated in Scheme 2A, treatment of 11 with
the appropriate Cbz-protected thiourea (12a–e) and EDCI led
to clean formation of protected guanidines 13a–e.[38,39] Remov-
al of Cbz and benzyl groups was achieved via hydrogenation
to yield the guanidine products 14a–e. For the synthesis of
the corresponding urea species, a series of Boc-protected
amines (15a–e) were generated according to a literature pro-
cedure.[40] Treatment of the Boc-protected amines with 2-chlor-
opyridine followed by the addition of trifluoromethanesulfonic
anhydride resulted in formation of the corresponding isocya-
nate intermediates that were immediately treated with 11 to
yield the protected ureas 16a–e. Removal of the benzyl
groups by hydrogenation provided ureas 17a–e (Scheme 2B).
The guanidine (14a–d) and urea (17a–d) series both incorpo-
rate different NG-substituents composed of simple alkyl chains
Table 1. Glycosidase inhibition values obtained for guanidines 14a–e and ureas 17a–e.
Compd
IC50 [mm][a]
Nar[f]
a-glu[b]
a-gal[c]
b-glu[d]
b-gal[e]
GBA[g]
GALC[g]
pH 7.0
pH 5.2
14a
14b
14c
14d
14e
17a
17b
17c
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
38.14Æ1.47
26.04Æ0.87
10.73Æ0.28
2.84Æ0.07
24.21Æ0.14
2.75Æ0.22
0.68Æ0.04
1.63Æ0.21
11.62Æ4.02
19.57Æ1.50
10.44Æ0.88
12.96Æ1.95
34.20Æ1.90
12.51Æ2.92
52.98Æ2.19
41.47Æ0.21
37.23Æ1.67
33.51Æ1.68
3.92Æ0.55
0.245Æ0.02
0.999Æ0.092
0.093Æ0.007
0.038Æ0.003
0.036Æ0.002
0.038Æ0.005
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
0.033Æ0.004
0.020Æ0.003
0.019Æ0.003
0.017Æ0.003
>100000
>100
>100
>100
>100
>100
>100
>100
>10
>10
>100
>100
>100
>100
>10
>10
>10
>10
>10
>10
>10
>10
17d
17e
NN-DNJ
>100
0.176Æ0.012
0.752Æ0.093
2.564Æ0.287
[a] Values are averages obtained from triple independent duplicate analysis of each compound. For ease of comparison, IC50 values are compared with
those of the reference compound NN-DNJ. [b] a-glucosidase (from baker’s yeast, Sigma G5003): 0.05 UmLÀ1, the activity was determined with p-nitrophen-
yl-a-d-glucopyranoside (0.7 mm final conc. in well) in sodium phosphate buffer (100 mm, pH 7.2). [c] a-galactosidase (from green coffee beans, Sigma
G8507): 0.05 UmLÀ1; a-galactosidase activity was determined with p-nitrophenyl-a-d-galactopyranoside (0.7 mm final conc. in well) in sodium phosphate
buffer (100 mm, pH 6.8). [d] b-glucosidase (from almond, Sigma G4511): 0.05 UmLÀ1; the activity was determined with p-nitrophenyl-b-d-glucopyranoside
(0.7 mm final conc. in well) in sodium acetate buffer (100 mm, pH 5.0). [e] b-galactosidase (from bovine liver, Sigma G1875): 0.05 UmLÀ1; activity was deter-
mined with p-nitrophenyl-b-d-galactopyranoside (0.7 mm final conc. in well) in sodium phosphate buffer (100 mm, pH 7.2). [f] Naringinase (from Penicillium
decumbens, Sigma N1385): 0.06 UmLÀ1. the activity was determined with p-nitrophenyl-b-d-glucopyranoside (0.7 mm final conc. in well) in sodium acetate
buffer (100 mm, pH 5.0). [g] b-glucocerebrosidase (GBA) and b-galactocerebrosidase (GALC) activities were determined using 4-methylumbelliferyl-b-d-glu-
copyranoside and 4-methylumbelliferyl-b-d-galactopyranoside, respectively, using assay conditions based on those previously reported.[41]
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ranging from eight to fourteen carbon atoms in length. In ad-
dition, bis-lipidated species 14e and 17e were also synthe-
sized as more representative substrate mimics for b-glucocere-
brosidase. We also confirmed that both the guanidine 14a–
e and the urea species 17a–e, are stable in aqueous solution
even after 12 days (see Supporting Information, Table S1).
The inhibitory potencies of DIX derivatives 14a–e and 17a–
e were determined against a panel of readily available glycosi-
dase enzymes as well as the human recombinant enzymes b-
glucocerebrosidase (GBA) and b-galactocerebrosidase (GALC).
With the plant enzymes, low micromolar inhibition of the b-
glycosidases was observed for 14a–e whereas no inhibition
was observed for the a-glycosidases, indicating an interesting
preference (Table 1). The corresponding ureas were even more
selective displaying inhibition of only the b-galactosidase from
bovine liver. We further evaluated the compounds against
human recombinant b-specific enzymes. Strikingly, potent in-
hibition was observed for guanidinium analogues 14a–
e against the human recombinant GBA with inhibition con-
stants measured in the low nanomolar range (IC50: 17–245 nm).
Despite the observed b-selectivity, the guanidinium com-
pounds did not inhibit the human recombinant galactose spe-
cific GALC, indicating a high degree of selectivity among the
human enzymes. In contrast, urea species 17a–e did not inhib-
it any of the human recombinant enzymes. Although the
reason for the dramatic difference between the inhibition pro-
file of the guanidine and urea analogues is not clear, the posi-
tive charge of the guanidinium group may point to an explan-
ation. As can be seen in Table 1, the length of the lipid ap-
pended to the guanidine moiety also has some effect on the
inhibition. The longer alkyl tails led to more potent inhibition.
To confirm the validity of our assays, we measured the often-
used reference compound NN-DNJ (2) and found it to have an
IC50 for GBA of 750 nm, which is similar to previous reports.[32]
Also of note is the pH dependence observed for GBA inhibition
by compounds 14a–e. In general, the IC50 values measured at
pH 7.0 were two- to three-fold lower than those measured at
pH 5.2 (Table 1).
Figure 3. A) The polar interactions of compound 14a (yellow carbon atoms)
with GBA residues. In blue we see numerous cation–p interactions of the
guanidinium group with Tyr313. Dashed yellow lines are the hydrogen
bonds from the sugar hydroxy groups and the ion–ion interaction between
the guanidinium group with Glu235. B) The polar interactions of NN-DNJ (2,
yellow carbon atoms) with GBA residues after docking and minimization. We
see fewer interactions of NN-DNJ with Tyr313 and none with Glu235.
To evaluate the effect of the substituted guanidinium
groups in comparison with a simple N-alkylated analogue of
DIX, we compared the C8-functionalized guanidine analogue
14a with the previously reported N-alkylated DIX derivative 5
bearing a C9 lipid. Using similar assay conditions, we measured
a near 7-fold lower IC50 value for compound 14a (245 nm) rela-
tive to that reported for 5 (1500 nm).[32] Similar IC50 values
were measured for NN-DNJ (2) in both studies indicating that
the above comparison is legitimate.[32] While previous studies
have indicated that N-alkylated DIX analogues are moderate
glycosidase inhibitors,[30] our data indicate that incorporating
an N-alkylated guanidino moiety can drastically improve inhibi-
tor potency.
ble of making additional cation–p interactions with the nearby
Tyr313 in comparison to the smaller amino function of NN-DNJ
(2). Furthermore, the guanidinium group engages in a hydro-
gen bond/salt bridge with nearby Glu235 that has no counter-
part in the structure of NN-DNJ (2). Both features likely contrib-
ute to the enhanced binding of 14a. This enhanced binding
was also the predicted outcome of the performed local dock-
ing simulation, which resulted in a calculated Ki of 155 nm for
14a and of 1150 nm for NN-DNJ (2).
Although much research is still needed to fully determine
their pharmacological chaperone function,[10] preliminary data
from experiments using Gaucher patient-derived fibroblasts
homozygous for N370S mutation, indicate that 14a possesses
a minor chaperone activity, somewhat weaker than the known
chaperone NN-DNJ (2) (see Supporting Information, Figure S1).
In conclusion, we report a series of stable iminosugar based
glycosidase inhibitors that contain either an exocyclic N-alkylat-
To gain insight into the possible binding mode(s) of guanidi-
nium compound 14a within the GBA active site, molecular
modeling was performed (Figure 3A,B; see the Supporting In-
formation for detailed description of docking experiments on
page S29). A comparison was made to the reported complex
of NN-DNJ (2). It is clear that the guanidinium of 14a is capa-
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[11] W. W. Kallemeijn, M. D. Witte, T. M. Voorn-Brouwer, M. T. C. Walvoort,
K. Y. Li, J. D. C. Codꢁe, G. A. Van Der Marel, R. G. Boot, H. S. Overkleeft,
J. M. F. G. Aerts, J. Biol. Chem. 2014, 289, 35351–35362.
[12] K.-Y. Li, J. Jiang, M. D. Witte, W. W. Kallemeijn, W. E. Donker-Koopman,
R. G. Boot, J. M. F. G. Aerts, J. D. C. Codꢁe, G. A. van der Marel, H. S. Over-
kleeft, Org. Biomol. Chem. 2014, 12, 7786–7791.
[13] P. Compain, O. R. Martin, Iminosugars: From Synthesis to Therapeutic Ap-
plications, Wiley, Chichester, 2007.
[14] M. Yagi, T. Kouno, Y. Aoyagi, H. Murai, J. Agric. Chem. Soc. Jpn. 1976, 50,
571–572.
[15] T. Sekioka, M. Shibano, G. Kusano, Nat. Med. 1995, 49, 332–335.
[16] A. B. Hughes, A. J. Rudge, Nat. Prod. Rep. 1994, 11, 135–162.
[17] R. C. Bernotas, G. Papandreou, J. Urbach, B. Oanem, Tetrahedron Lett.
1990, 31, 3393–3396.
[18] T. M. Jespersen, M. Bols, Tetrahedron 1994, 50, 13449–13460.
[19] E. M. Sꢂnchez-Fernꢂndez, J. M. G. Fernandez, C. O. Mellet, Chem.
Commun. 2016, 52, 5497–5515.
[20] A. T. Ghisaidoobe, R. J. B. H. N. Van Den Berg, S. S. Butt, A. Strijland, W. E.
Donker-koopman, S. Scheij, A. M. C. H. Van Den Nieuwendijk, G.
Koomen, A. Van Loevezijn, M. Leemhuis, et al., J. Med. Chem. 2014, 57,
9096–9104.
[21] A. Hottin, D. W. Wright, G. J. Davies, J. B. Behr, ChemBioChem 2015, 16,
277–283.
ed guanidinium or urea moiety. Interestingly, the DIX-derived
ureas (17a–e) were selective inhibitors of b-galactosidase from
bovine liver. By comparison, the guanidinium analogues (14a–
e) were found to be highly selective inhibitors of the human b-
glycosidase GBA. Our study clearly indicates that the addition
of a guanidinium moiety leads to more potent inhibition of
GBA when compared to the reported alkylated amine com-
pound (5). The inhibitory potency is increased with longer
alkyl substituents with the measured inhibition constants rang-
ing from 245 nm to 19 nm for compounds 14a–d. In addition,
the bis-lipidated analogue 14e served as a close substrate
mimic for b-glucocerebrosidase and proved to be on par with
our most potent inhibitors 14b–d with an IC50 of 17 nm. Dock-
ing studies also point to additional cation–p interactions, as
well as an extra hydrogen bond/salt bridge to the guanidinium
group, as a plausible explanation for the enhanced glycosidase
inhibition exhibited by 14a–e. More comprehensive studies ex-
amining the potential for the DIX analogues reported here, to
serve as pharmacological chaperones will be reported in due
course.
[22] A. R. Sawkar, W.-C. Cheng, E. Beutler, C.-H. Wong, W. E. Balch, J. W. Kelly,
Proc. Natl. Acad. Sci. USA 2002, 99, 15428–15433.
[23] G. Godin, P. Compain, O. R. Martin, K. Ikeda, L. Yu, N. Asano, Bioorg.
Med. Chem. Lett. 2004, 14, 5991–5995.
[24] N. T. Patil, S. John, S. G. Sabharwal, D. D. Dhavale, Bioorg. Med. Chem.
2002, 10, 2155–2160.
Acknowledgements
[25] G. Pandey, M. Kapur, M. I. Khan, S. M. Gaikwad, Org. Biomol. Chem.
2003, 1, 3321.
[26] H. Han, Tetrahedron Lett. 2003, 44, 1567–1569.
No competing financial interests are declared. Financial support
provided by the Slovenian Human Resources Development and
Scholarship for Scientific Research (PhD grant to A.S.).
[27] H. Ouchi, Y. Mihara, H. Takahata, J. Org. Chem. 2005, 70, 5207–5214.
[28] C. Parmeggiani, S. Catarzi, C. Matassini, G. D’Adamio, A. Morrone, A.
Goti, P. Paoli, F. Cardona, ChemBioChem 2015, 16, 2054–2064.
[29] A. E. Mccaig, B. Chomier, R. H. Wightman, J. Carbohydr. Chem. 1994, 13,
397–407.
[30] G.-N. Wang, G. Reinkensmeier, S.-W. Zhang, J. Zhou, L.-R. Zhang, L.-H.
Zhang, T. D. Butters, X.-S. Ye, J. Med. Chem. 2009, 52, 3146–3149.
[31] X. Zhu, K. A. Sheth, S. Li, H.-H. Chang, J.-Q. Fan, Angew. Chem. Int. Ed.
2005, 44, 7450–7453; Angew. Chem. 2005, 117, 7616–7619.
[32] P. Compain, O. R. Martin, C. Boucheron, G. Godin, L. Yu, K. Ikeda, N.
Asano, ChemBioChem 2006, 7, 1356–1359.
Conflict of interest
The authors declare no conflict of interest.
Keywords: Gaucher disease
·
glycosidase inhibitors
·
guanidinium · iminosugars · pharmacological chaperones · b-
glucocerebrosidase
[33] N. I. Martin, J. J. Woodward, M. A. Marletta, Org. Lett. 2006, 8, 4035–
4038.
[34] R. Kooij, H. M. Branderhorst, S. Bonte, S. Wieclawska, N. I. Martin, R. J. Pi-
eters, MedChemComm 2013, 4, 387.
[1] G. Horne, F. X. Wilson, J. Tinsley, D. H. Williams, R. Storer, Drug Discovery
Today 2011, 16, 107–118.
[2] J. Churruca, V. Luis, E. Luna, J. Ruiz-Galiana, V. Manuel, Diabetes Metab.
Syndr. Obes. 2008, 1, 3–11.
[3] X. Gao, H. Yang, Y. Xu, Y. Xiong, G. Wang, X. Ye, J. Ye, Int. Immunophar-
macol. 2014, 23, 688–695.
[4] D. Ruhela, P. Chatterjee, R. A. Vishwakarma, Org. Biomol. Chem. 2005, 3,
1043–1048.
[5] S. Hussain, J. L. Miller, D. J. Harvey, Y. Gu, P. B. Rosenthal, N. Zitzmann,
J. W. Mccauley, J. Antimicrob. Chemother. 2015, 70, 136–152.
[6] G. N. Wang, Y. Xiong, J. Ye, L. H. Zhang, X. S. Ye, ACS Med. Chem. Lett.
2011, 2, 682–686.
[7] D. A. Kuntz, S. Nakayama, K. Shea, H. Hori, Y. Uto, H. Nagasawa, D. R.
Rose, ChemBioChem 2010, 11, 673–680.
ˇ
ˇ
[35] A. Sevsek, M. Celan, B. Erjavec, L. Q. van Ufford, J. S. ToraÇo, E. E. Moret,
R. J. Pieters, N. I. Martin, Org. Biomol. Chem. 2016, 14, 8670–8673.
[36] J. Lehmann, B. Rob, Carbohydr. Res. 1995, 272, C11–C13.
[37] R. G. Boot, M. Verhoek, W. Donker-Koopman, A. Strijland, J. Van Marle,
H. S. Overkleeft, T. Wennekes, J. M. F. G. Aerts, J. Biol. Chem. 2007, 282,
1305–1312.
[38] N. I. Martin, W. T. Beeson, J. J. Woodward, M. A. Marletta, J. Med. Chem.
2008, 51, 924–931.
[39] N. I. Martin, R. M. J. Liskamp, J. Org. Chem. 2008, 73, 7849–7851.
[40] C. Helgen, C. G. Bochet, J. Org. Chem. 2003, 68, 2483–2486.
[41] A. Trapero, P. Gonzꢂlez-Bulnes, T. D. Butters, A. Llebaria, J. Med. Chem.
2012, 55, 4479–4488.
Manuscript received: January 25, 2017
Revised: March 9, 2017
[8] F. M. Platt, Nature 2014, 510, 68–75.
[9] G. Parenti, G. Andria, K. J. Valenzano, Mol. Ther. 2015, 23, 1138–1148.
[10] M. Convertino, J. Das, N. V. Dokholyan, ACS Chem. Biol. 2016, 11, 1471–
1489.
Accepted Article published: March 9, 2017
Final Article published: && &&, 0000
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ˇ
ˇ
ˇ
Sweet GBA inhibitors! A series of 1-N-
iminosugars were synthesized to supply
the need for glycosidase inhibitors that
are both highly potent and selective for
b-glycosidases. These iminosugar inhibi-
tors differ from the currently available
inhibitors in that they possess a guani-
dine or urea group at the endocyclic
position of the 1,5-dideoxy-1,5-imino-d-
xylitol ring. The guanidine series was
found to be extremely potent and
highly specific against the b-glycosidas-
es, with IC50 values in the nanomolar
range.
A. Sevsek, L. Srot, J. Rihter, M. Celan,
L. Q. van Ufford, E. E. Moret, N. I. Martin,*
R. J. Pieters*
&& – &&
N-Guanidino Derivatives of 1,5-
Dideoxy-1,5-imino-d-xylitol are
Potent, Selective, and Stable Inhibitors
of b-Glucocerebrosidase
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