Heteroaryl-O-glucosides as novel sodium glucose co-transporter 2 inhibitors. Part 1

Article abstract of DOI:10.1016/j.bmcl.2005.08.067

A series of benzo-fused heteroaryl-O-glucosides was synthesized and evaluated in SGLT1 and 2 cell-based functional assays. Indole-O-glucoside 10a and benzimidazole-O-glucoside 18 exhibited potent in vitro SGLT2 inhibitory activity.

Full text of DOI:10.1016/j.bmcl.2005.08.067

Bioorganic & Medicinal Chemistry Letters 15 (2005) 5202–5206
Heteroaryl-O-glucosides as novel sodium glucose
co-transporter 2 inhibitors. Part 1
Xiaoyan Zhang,* Maud Urbanski, Mona Patel, Roxanne E. Zeck,
Geoffrey G. Cox, Haiyan Bian, Bruce R. Conway, Mary Pat Beavers,
Philip J. Rybczynski and Keith T. Demarest
Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 1000 Rt. 202, PO Box 300, Raritan, NJ 08869, USA
Received 28 June 2005; revised 18 August 2005; accepted 22 August 2005
Available online 28 September 2005
Abstract—A series of benzo-fused heteroaryl-O-glucosides was synthesized and evaluated in SGLT1 and 2 cell-based functional
assays. Indole-O-glucoside 10a and benzimidazole-O-glucoside 18 exhibited potent in vitro SGLT2 inhibitory activity.
Ó 2005 Elsevier Ltd. All rights reserved.
Controlling levels of fasting and postprandial plasma
glucose is the first goal of therapy for non-insulin depen-
dent diabetes mellitus (NIDDM). Since plasma glucose
is continuously filtered in the kidney glomerulus and is
subsequently transepithelially reabsorbed by the sodi-
um-glucose co-transporters (SGLTs) in the proximal
tubules, a therapeutic agent which blocks glucose reab-
sorption in the kidney should provide a novel treatment
for NIDDM.1–3 There is evidence that at least three iso-
forms of SGLT are present in the human body, referred
to as SGLT1 through SGLT3.4 SGLT1 is present pri-
marily in the intestinal cells, whereas SGLT2 is found
predominantly in the epithelium of the kidney. Glucose
absorption in the intestine is mediated by SGLT1, a
high-affinity low-capacity transporter. Renal reabsorp-
tion of glucose is mediated by both SGLT1 and SGLT2
on the luminal side of the proximal tubule of the kidney.
SGLT2 is a low-affinity high-capacity transporter and is
likely responsible for the bulk of glucose reabsorption in
the renal proximal tubule. SGLT3, formerly known as
SAAT1, may serve as a glucose sensor in cholinergic
neurons, skeletal muscle, and other tissues. SGLT4 is
a low-affinity transporter that may act as a mannose/
fructose transporter in the intestine and kidney.4b Inhi-
bition of SGLTs in diabetic patients would be expected
to normalize plasma glucose by reducing glucose uptake
at the intestine (SGLT1) and promoting glucose excre-
tion into the urine (SGLT2).5 Phlorizin is a natural
SGLT inhibitor. Compound 1, (T1095A), a phlorizin
analogue, inhibited both SGLT1 and SGLT2, and dem-
onstrated efficacy in numerous animal models as an
antidiabetic agent.5 Recently, we reported structure–ac-
tivity relationship (SAR) studies of compound 1 and
found potent and selective SGLT2 inhibitors.6 As part
of our ongoing SAR studies, we designed and synthe-
sized a series of novel compounds different from both
the core structure of compound 1 and other reported
structures.7 The key modification was to replace the ke-
tone/phenol portion of 1 with a heteroaryl ring, wherein
the 10 NH group of the heteroaryl ring mimics the 60 OH
group in compound 1. Since there is no clinical evidence
to show whether a selective SGLT2 inhibitor or a mixed
SGLT1/SGLT2 inhibitor is better for treatment of dia-
betes, we were interested in developing both types of
inhibitors to better understand the mechanism of action.
Herein, we describe the initial SAR surrounding a novel
series of heteroaryl-O-glucosides with potent in vitro
SGLT2 inhibitory activity.
R1 1'
N
X
Y
OH
O
O
6'
Ar
R2
O
6'
O
H3C
4'
OH
OH
O
OH
OH
O
HO
HO
OH
OH
Keywords: SGLT; Heteroaryl-O-glucosides.
*
X = CH, or N or C=O
Y = C, or N
R1 or R2 = H or alkyl groups
1
Corresponding author. Tel.: +1 908 704 5232; fax: +1 908 203 4861;
e-mail: xzhang11@prdus.jnj.com
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.08.067

X. Zhang et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5202–5206
Table 1. In vitro activity to inhibit SGLT2
5203
Ar
O
OH
OH
O
HO
OH
Compound
Ar
IC50 SEM (lM)
SGLT1
SGLT2
OH
O
N
N
1
0.139 0.013
0.011 0.002
0.491 0.056
0.458 0.061
0.532 0.047
0.754 0.069
0.024 0.004
0.067 0.003
0.163 0.019
0.394 0.013
0.039 0.001
0.380 0.022
O
O
H3C
H3C
H3C
Et
HN
6a
52%a
HN
6b
48%a
O
HN
N
6c
0%a
O
H3C
N
N
6d
47%a
O
H3C
HN
10a
10b
10c
10d
18
0.145 0.011
0.198 0.002
0.611 0.091
3.05 0.23
0.718 0.126
40%a
O
H3C
N
O
HN
OCH3
HN
H3C
N
OCH3
N
O
N
N
N
19
OCH3
(continued on next page)

5204
X. Zhang et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5202–5206
Table 1 (continued)
Compound
Ar
IC50 SEM (lM)
SGLT1
SGLT2
18%a
O
HN
N
20
25
0%a
OCH3
O
HN
0%a
22%a
O
H3C
a Inhibition at a screening concentration of 10 lM.
OBn O
c, d
a
R1
R1
N
R2
OBn
O
N
N
N
Ar
OH
O
HO
O
Ar
h, i
3a
g
Ar
R2
O
R2
R
R2
OH
OH
R2
OH
OH
OH
MOMO
O
2
4
5
HO
b
R2 = CH3 or C2H5
1 = H or CH3
R2 = CH3 or C2H5
c, e, f
R2
OMOM
OH
6a-d
3b
Scheme 1. Reagents and conditions: (a) BnBr (4 equiv), K2CO3 (10 equiv), DMF; (b) MOM Br (2 equiv), K2CO3 (5 equiv), CH3CN; (c) ArCHO,
KOH, EtOH; (d) H2 (45 psi), 10% Pd/C, EtOH/EtOAc (1:1); (e) H2 (15 psi), 10% Pd/C, EtOAc; (f) concn HCl, i-PrOH/dioxane; (g) NH2-NHR1,
HOCH2CH2OH, 160 °C; (h) 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl bromide (2 equiv), K2CO3 (5 equiv), acetone; (i) K2CO3, MeOH.
4 cyclized with hydrazine or methyl hydrazine to form
1H-indazole 5 in moderate yield.8 Glycosylation of 5
using the biphasic conditions previously described to
prepare analogues of compound 1 was not successful,
probably due to the poor solubility of aglycone 5 in
either phase.6 Glycosylation could be achieved with
2 equiv of 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl
bromide and 5 equiv of K2CO3 in acetone for 24 h. Sub-
sequent saponification of the acetyl groups provided
compounds 6a–d in 20–30% yield for the two steps.9a
No N-glucoside of 5 was isolated from the reaction un-
der the conditions investigated. The last two steps have
Our initial attempt to synthesize indazole 6a (Table 1)
by cyclization of compound 1 with hydrazine8 did not
yield the desired product. Thus, conjugated indazoles
6a–d were prepared from resorcinol derivatives 26
(Scheme 1). Aldol condensation of 3a with 2,3-
dihydrobenzofuran-5-carbaldehyde provided an a,b-un-
saturated ketone. Hydrogenation at 45 psi produced
dihydrochalcone 4 (Ar = 2,3-dihydrobenzofuran). Alter-
natively, aldol condensation of 3b with benzofuran-5-
carbaldehyde, selective hydrogenation of the a,b-unsat-
urated ketone at 15 psi, and deprotection with HCl gave
dihydrochalcone 4 (Ar = benzofuran). Dihydrochalcone
O
O
Et2N
N
Et2N
1
N
R
b, c
d, e
N
CHO
OBn
Ar
a
1
R
Ar
2
2
1
R
R
OH
N
R = H
2
R
O
CHO
OBn
8
9a
OH
OH
H C
O
3
2
R
N
HO
b, c
1
d, f
Ar
OH
1
2
R
= CH
3
7a R = H, R = H
2
1
2
R
OH
7b R = CH , R = H
3
10a-d
1
2
7c R = H, R = CH
9b
3
Scheme 2. Reagents and conditions: (a) N,N-diethylcarbamoyl chloride, NaH, THF; (b) ArCH = PPh3, THF, ꢀ78 °C to rt; (c) H2 (15 psi), 10%
Pd/C, EtOH/EtOAc; (d) 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl bromide, K2CO3, acetone; (e) KOH (25%), EtOH, reflux; (f) K2CO3, MeOH.

X. Zhang et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5202–5206
5205
application to other heteroaromatic systems in this
study.
nitro group and borane reduction of the amide fortu-
itously provided a 3:2 ratio of 13 and 14, separable by
flash chromatography. The benzimidazole system was
formed by treatment of compound 13 with triethylor-
thoformate. Subsequent deprotection of the phenol
group provided the benzimidazole aglycone 15. Treat-
ment of compound 14 with sodium nitrite provided
the benztriazole aglycone 16. Cyclization of 13 with tri-
phosgene, followed by deprotection of the phenol group,
led to the benzimidazolone aglycone 17. Glycosylation
of aglycones 15–17 under the conditions described
above provided analogues 18–20 in low to moderate
yields.9c
Scheme 2 depicts the synthesis of indole analogues 10a–
d. Aglycones 9a and b were obtained from indolecarbal-
dehydes 7a–c10 by the Wittig reaction and hydrogena-
tion at 15 psi. Glycosylation of aglycone 9 was carried
out under the conditions described above to provide
tetra-acetylglucosides in yields of 40–75%. Lithium
hydroxide-promoted glycosylation of indoles has been
reported,11 but did not afford higher yields. Saponifica-
tion of the acetyl groups provided compounds 10a–d in
20–30% yield for the two steps.9b
Benzimidazole 18, benztriazole 19, and benzimidazolone
20 were constructed from 12, which was prepared by
acylation and silylation of commercially available 2-
amino-3-nitrophenol (Scheme 3). Hydrogenation of the
In Scheme 4, the intermediate 23 was prepared from
compound 21 using a synthetic approach that was sim-
ilar to that outlined for the formation of the dihydroch-
alcone 4 described in Scheme 1. Cyclization of 23 with
O
O
HN
Ar
HN
N
Ar
N
g, h
O
OH
OH
OH
O
17
HO
OH
e, f
20
NH2
NO2
NO2
H
N
NH2
H
N
H
N
NH2
a, b
Ar
Ar
Ar
c, d
O
+
OH
OTBS
OH
OTBS
i, f
11
12
13
14
N
N
Ar
N
N
j
Ar
N
O
N
N
N
O
Ar
Ar
g, h
OH
OH
N
N
g, h
O
OH
OH
O
HO
HO
OH
OH
OH
OH
15
16
19
1
Scheme 3. Reagents: (a) ArCH2COCl, Et3N, CH2Cl2; or ArCH2CO2H, EDCI, HOBt, DMF; (b) TBSCl, imidazole; (c) H2 (15 psi), 10% Pd/C, EtOH;
(d) BH3ÆTHF; (e) CDI or triphosgene, THF; (f) TBAF, THF; (g) 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl bromide (2 equiv), K2CO3 (5 equiv),
acetone; (h) K2CO3, MeOH; (i) HC(OEt)3, p-TSA; (j) NaNO2, HCl (3 N).
O
O
HN
Bn
Bn
Bn
Bn
N
O
NH2
O
HN
N
O
Ar
a
b, c
f, g
d, e
CH3
OH
Ar
Ar
CH3
OMOM
H3C
O
OH
OH
H3C
H3C
H3C
OMOM
H3C
OH
O
HO
21
22
23
24
OH
25
Scheme 4. Reagents: (a) MOMBr, K2CO3, acetone; (b) ArCHO, KOH, EtOH; (c) H2 (45 psi), 10% Pd/C, DMAP, EtOH; (d) (EtO)2P(O)CH2CO2Et,
NaH, THF; (e) concn HCl, i-PrOH, dioxane; (f) 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl bromide (2 equiv), K2CO3 (5 equiv) acetone, DMF;
(g) K2CO3, MeOH.

5206
X. Zhang et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5202–5206
Tsujihara, K. Chem. Pharm. Bull. 1998, 46, 22; (c)
Tsujihara, K.; Hongu, M.; Saito, K.; Kawanishi, H.;
Kuriyama, K.; Matsumoto, M.; Oku, A.; Ueta, K.; Tsuda,
M.; Saito, A. J. Med. Chem. 1999, 42, 5311; (d) Doggrell,
S. A.; Castaner, J. Drugs Future 2001, 26, 750; (e) Kumiko,
N.; Koichiro, Y.; Tetsuya, A.; Yoshimasa, O.; Nobuyuki,
S.; Mika, U.; Akiko, T.; Naoko, S.; Akika, O.; Kinsuke,
T. Clin. Exp. Pharmacol. Physiol. 2002, 29, 386.
the ylide derived from triethylphosphonoacetate affor-
ded a 1H-quinolin-2-one in 31% yield.12 Subsequent
deprotection of the phenol group provided aglycone
24. Glycosylation and deprotection as described above
gave analogue 25 in low yield.9d
All compounds were screened in a cell-based SGLT
functional assay,13 and IC50 values are presented in Ta-
ble 1. The indazole analogues 6a–d showed only moder-
ate inhibitory activity toward SGTL2, but were selective
for SGLT2 compared to the parent compound 1.
Replacement of the benzofuran in analogue 6a with
2,3-dihydrobenzofuran in compound 6b did not change
the SGLT2 inhibitory activity. However, the benzofuran
moiety could cause unwanted P450 inhibition of 1.
6. Dudash, J., Jr.; Zhang, X.; Zeck, R. E.; Johnson, S. G.;
Cox, G. G.; Conway, B. R.; Rybczynski, P. J.; Demarest,
K. T. Bioorg. Med. Chem. Lett. 2004, 14, 5121.
7. (a) Ohsumi, K.; Matsueda, H.; Hatanaka, T.; Hirama, R.;
Umemura, T.; Oonuki, A.; Ishida, N.; Kageyama, Y.;
Maezono, K.; Kondo, N. Bioorg. Med. Chem. Lett. 2003,
13, 2269; (b) Nishimura, T.; Fujikura, H.; Fushimi, N.;
Tatani, K.; Katsuno, K.; Isaji, M. WO03/000712, 2003;
Chem. Abstr. 2003, 138, 49945; (c) Nishimura, T.; Fush-
imi, N.; Fujikura, H.; Katsuno, K.; Komatsu, Y.; Isaji, M.
WO02/068439; Chem. Abstr. 2002, 137, 232854; (d)
Fujikura, H.; Fushimi, N.; Nishimura, T.; Tatani, K.;
Katsuno, K.; Hiratochi, M.; Tokutake, Y.; Isaji, M.
WO01/68660; Chem. Abstr. 2003, 135, 242456; (e) Wash-
burn, W. N.; Ellsworth, B.; Meng, W.; Wu, G.; Sher, P.
M. US03/0114390; Chem. Abstr. 2003, 139, 36736.
8. Boehm, H.; Boehringer, M.; Bur, D.; Gmuender, H.;
Huber, W.; Klaus, W.; Kostrewa, D.; Kuehne, H.;
Luebbers, T.; Meunier-Keller, N.; Mueller, F. J. Med.
Chem. 2000, 43, 2664.
The SAR of compound 1 suggested that the phenol
group at the 60-position participates in a hydrogen
bonding interaction,5b,6 which supported the computa-
tional hypotheses by Weilert-Badt et al.14 However, this
trend was not observed with the heterocyclic analogues.
Good activity was preserved when the N-1 position of
the indole was alkylated as in compound 10b. Likewise,
the lack of hydrogen bonding ability at the N-1 position
of the benzimidazoles 18 did not diminish SGLT2 inhib-
itory activity. In addition, urea 20 and lactam 25 showed
much weaker SGLT2 inhibitory activity than the other
scaffolds, though this may be due to steric effects.
9. All compounds provided satisfactory spectral data (1H
NMR, LCMS) and were homogeneous by TLC. Detailed
experimental procedures have been published in the
following patent applications: (a) Patel, M.; Rybczynski,
P.; Urbanski, M.; Zhang, X. WO05/011592A2; Chem.
Abstr. 2005, 142, 198298; (b) Beavers, M. P.; Patel, M.;
Urbanski, M.; Zhang, X. WO05/012243A2; Chem Abstr.
2005, 142, 219489; (c) Urbanski, M. WO05/012242A2;
Chem Abstr. 2005, 142, 219492.
In summary, we have demonstrated that the ketone/phe-
nol portion of compound 1 can be replaced with a ben-
zo-fused heterocycle while retaining the desired in vitro
SGLT2 inhibitory activity. Further modification of this
series will be reported in due course.
10. Compound 7a is commercially available. Compound 7b
was prepared by methylation of the sodium salt of 7a with
methyl iodide in DMF. Compound 7c was prepared using
literature procedures: (a) Blair, J. B.; Kurrasch-Orbaugh,
D.; Marona-Lewicka, D.; Cumbay, M. G.; Watts, V. J.;
Barker, E. L.; Nichols, D. E. J. Med. Chem. 2000, 43,
4710; (b) Fresneda, P. M.; Molina, P.; Bleda, J. A.
Tetrahedron 2001, 57, 2355.
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13. CHO-K1 cells overexpressing human SGLT2 or SGLT1
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treated with compound in the absence or presence of NaCl
for 15 min. Cells were then labeled with [14C]a-methyl-
glucopyranoside (AMG)—a non-metabolizable glucose
analogue specific for sodium-dependent glucose transport-
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with ice-cold PBS. Cells were then solubilized and Na-
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