Discovery of a potent, low-absorbable sodium-dependent glucose cotransporter 1 (SGLT1) inhibitor (TP0438836) for the treatment of type 2 diabetes

Article abstract of DOI:10.1016/j.bmcl.2018.09.035

The design and synthesis of a novel class of low-absorbable SGLT1 inhibitors are described. To achieve low absorption in the new series, we performed an optimization study based on a strategy to increase TPSA. Fortunately, the optimization of an aglycon m

Full text of DOI:10.1016/j.bmcl.2018.09.035

Accepted Manuscript
Discovery of a Potent, Low-Absorbable Sodium-Dependent Glucose Cotrans-
porter 1 (SGLT1) Inhibitor (TP0438836) for the Treatment of Type 2 Diabetes
Shoichi Kuroda, Yohei Kobashi, Takahiro Oi, Hideaki Amada, Lisa Okumura-
Kitajima, Fusayo Io, Koji Yamamto, Hiroyuki Kakinuma
PII:
S0960-894X(18)30777-7
https://doi.org/10.1016/j.bmcl.2018.09.035
BMCL 26056
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
22 June 2018
10 September 2018
27 September 2018
Please cite this article as: Kuroda, S., Kobashi, Y., Oi, T., Amada, H., Okumura-Kitajima, L., Io, F., Yamamto, K.,
Kakinuma, H., Discovery of a Potent, Low-Absorbable Sodium-Dependent Glucose Cotransporter 1 (SGLT1)
Inhibitor (TP0438836) for the Treatment of Type 2 Diabetes, Bioorganic & Medicinal Chemistry Letters (2018),
doi: https://doi.org/10.1016/j.bmcl.2018.09.035
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Discovery of a Potent, Low-Absorbable Sodium-Dependent Glucose Cotransporter 1 (SGLT1)
Inhibitor (TP0438836) for the Treatment of Type 2 Diabetes
Shoichi Kurodaa,*, Yohei Kobashia, Takahiro Oib, Hideaki Amadac, Lisa Okumura-Kitajimad, Fusayo
Ioe, Koji Yamamtod, Hiroyuki Kakinuma a,*
a Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd. ; 1-403 Yoshino-cho, Kita-ku, Saitama
331-9530, Japan.
b Pharmaceutical Science Laboratories, Taisho Pharmaceutical Co., Ltd. ; 1-403 Yoshino-cho,
Kita-ku, Saitama 331-9530, Japan.
c
Development Management, Taisho Pharmaceutical Co., Ltd, 3-24-1, Takada, Toshima-ku, Tokyo
170-8633, Japan.
d Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd. ; 1-403 Yoshino-cho, Kita-ku,
Saitama 331-9530, Japan.
e Medical Affairs Group, Taisho Toyama Pharmaceutical Co., 3-25-1, Takada, Toshima-ku, Tokyo
170-8635, Japan.
Abstract
The design and synthesis of a novel class of low-absorbable SGLT1 inhibitors are described. To
achieve low absorption in the new series, we performed an optimization study based on a strategy to
increase TPSA. Fortunately, the optimization of an aglycon moiety and a side chain of the distal
aglycon moiety led to the identification of compound 30b as a potent and low-absorbable SGLT1
inhibitor. Compound 30b showed a desirable PK profile in Sprague-Dawley (SD) rats and a
favorable glucose-lowering effect in diabetic rats.
The number of people with type 2 diabetes mellitus (T2DM) is increasing. The International
Diabetes Federation estimates that approximately 415 million adults have diabetes, and this total is
expected to rise to 642 million by 2040. T2DM can cause serious health problems such as
cardiovascular disease, blindness, kidney failure and lower limb amputation. Recently, the
association between sugar intake, particularly from sugar-sweetened beverages, and the risk of
T2DM has been discussed.1 In 2014, the World Health Organization (WHO) issued new
recommendations to limit sugar intake. Maintaining blood glucose levels is important for the
prevention of T2DM.
Sodium-dependent glucose cotransporters (SGLTs) have attracted considerable attention as a
new target for T2DM. SGLT2 is expressed mostly in early renal proximal tubules and is responsible

for >90% of the renal reabsorption of filtered glucose (160-180 g/day).2,3,4 In fact, several SGLT2
inhibitors including dapagliflozin,5 canagliflozin,6 empagliflozin,7 ipragliflozin,8 luseogliflozin9 and
tofogliflozin10 have been approved. On the other hand, SGLT1 plays an important role in glucose
absorption from the intestinal lumen into the epithelial cells of the small intestine. In fact, small
intestinal SGLT1 mRNA expression and intestinal glucose uptake were increased in patients with
T2DM. Therefore, creating an SGLT1 inhibitor is an attractive option for the treatment of T2DM.11
Some glucose derivatives have been reported as SGLT1 inhibitors.12,13,14
We have focused on low-absorbable SGLT1 inhibitors that suppress glucose absorption in the
small intestine to control blood glucose with minimal side effects. However, a systemic and orally
available SGLT1 inhibitor might have an overly strong blood glucose lowering effect because of the
suppression of glucose absorption from the intestine and the excretion of urinary glucose via the
inhibition of SGLT1 on the distal proximal tubules in the kidney, thereby inducing hypoglycemia.
Furthermore, SGLT1 is also expressed in the heart, where its function is unclear.15,16
We previously reported the structure-activity relationship (SAR) of C-phenyl 1-thio-D-glucitol
derivatives with selective SGLT2 inhibitory activities.9 We found that the SGLT2 selectivity to
SGLT1 was lowered while the SGLT2 inhibition potency was maintained when R1 of compound 1
was a hydroxyl group. Thus, we selected compound 2 as a starting core structure for a moderate
SGLT1 inhibitor.
Next, low absorbability was imparted by introducing a side chain with a highly water-soluble
polar functional group into R4 of the distal aglycon moiety. Furthermore, conversion from
thioglucose to glucose was performed from the viewpoint of reducing both lipophilicity and cost
(Figure 1).
Figure 1. Strategy for creating a low-absorbable SGLT1 inhibitor.
Herein, we optimized the substituents on the aglycon moiety of 2 to improve the SGLT1
inhibition activity (Figure 1). We describe the synthesis and structure-activity relationships (SARs)
of this new series of C-phenyl 1-thio-D-glucitol derivatives and C-phenyl D-glucitol derivatives,
focusing on improving the SGLT1 inhibition potency and decreasing absorbability, to create a
low-absorbable functional SGLT1 inhibitor.
The C-phenyl 1-thio-D-glucitol derivatives 4a-4c, shown in Table 1, were synthesized as
described in our previous paper.9
The synthesis of the C-phenyl 1-thio-D-glucitol derivatives 14a-14e, also shown in Table 1, is

shown in Scheme 1. For the synthesis of compounds 14a-14e, commercially available
4-hydroxy-2-methyl-acetophenone (5) was protected by a benzyl group using benzyl bromide and
then oxidatively brominated using NaBr in the presence of OXONE® to generate 6. The carboxyl
group of 6 was converted to aldehyde via a Winreb amide reduction to yield 7. After the halogen
lithium exchange of compounds 8a-8e, these compounds were coupled with 7, leading to 9a-9e.
Reduction of the hydroxyl group of 9a-9e using triethylsilane and boron trifluoride diethyletherate
produced aglycon 10a-10e. 12a-12e were obtained by adding thiolactone 11, synthesized as
described in our previous paper, to the THF solution of Grignard reagents prepared from compounds
10a-10e and magnesium powder. The resulting hydroxyl group of 12a-12e was reduced
β-stereoselectively to yield compounds 13a-13e. Finally, the benzyl group of 13a-13e was removed
by catalytic hydrogenation with palladium hydroxide under a hydrogen atmosphere to yield 14a-14e.
Scheme 1. (a) BnBr, K2CO3, TBAI, DMF, rt; (b) NaBr, OXONE®, acetone-H2O, rt; (c) (COCl)2,
DMF(cat.), CHCl3, rt, then N-methoxy-N-methylamine hydrochloride, Et3N, rt ; (d) LiAlH4, THF, 0˚C; (e)
8a-8e, n-BuLi, THF, -78˚C, then 7; (f) Et3SiH, BF3OEt2, CH3CN/CHCl3, 0˚C; (g) Mg, THF; (h) Et3SiH,
BF3OEt2, CH3CN/CHCl3, -15˚C; (i) Pd(OH)2/H2, EtOH, rt.
The synthesis of the C-phenyl 1-thio-D-glucitol derivatives 22c-22h is shown in Scheme 2.
Compound 7 was protected by an acetal group using ethylene glycol under acidic conditions,
yielding 15. 17a and 17b were obtained by adding thiolactone 16a or commercially available lactone
16b to lithium reagents prepared from 15 and n-BuLi. The removal of the acetal group of 17a and

17b yielded 18a and 18b, respectively. 1,4-Dibromobenzene was mono-lithiated using n-BuLi and
coupled with 18a and 18b, followed by the reduction of the hydroxyl group at the anomeric position
to yield 19a and 19b, respectively. A subsequent Mizoroki-Heck reaction of 19a, 19b with
vinylacetate under microwave irradiation yielded 20a and 20b, respectively. 21c-21h were obtained
by condensing 20a, 20b and the corresponding amines using water soluble carbodiimide
hydrochloride. Finally, the benzyl group removal and double bond reduction of 21c-21h were
performed under conditions similar to those used for 13a-13e in Scheme 1 to yield the desired
products 22c-22h.
Scheme 2. (a) p-TsOH, ethylene glycol, PhMe, reflux; (b) n-BuLi, THF, -78˚C, then 16a,16b; (c) 6NHCl,
THF; (d) 1,4-dibromobenzene, n-BuLi, THF, -78˚C, (e) Et3SiH, BF3OEt2, CH3CN/CHCl3, 0˚C; (f) vinyl
acetate, Pd(OAc)2, (o-tolyl)3P, Et3N, MeCN, 120˚C; (g) amine, WSCI-HCl, HOBt, CHCl3, rt; (h)
Pd(OH)2/H2, EtOH, rt.
Scheme 3 shows the synthesis of compounds 25a-25c. Mizoroki-Heck coupling of 19b with

allyl urea derivatives 23a-23c under heating yielded 24a-24c. The benzyl group removal and double
bond reduction of 24a-24c were performed under conditions similar to those used for 13a-13e in
Scheme 1 to yield the desired products 25a-25c.
Scheme 3. (a) Pd(OAc)2, (o-tolyl)3P, Et3N, MeCN, 120˚C; (b) Pd(OH)2/H2, EtOH, rt.
Scheme 4 shows the synthesis of compounds 30a and 30b. Compound 27 was obtained by
adding 18b to aryl lithium prepared from 26. The hydroxyl groups of 27 were reduced at the same
time to yield 28 as a β-C-glucoside. The trityl group removal of 28 was removed under acidic
conditions to yield 29. The preparations of 30a and 30b were performed by the condensation of 29
with the corresponding amines followed by the removal of the benzyl group under the same
conditions as those used for 13a-13e in Scheme 1.
Scheme 4. (a) 26, n-BuLi, THF, then 18b, -78˚C, (b) Et3SiH, BF3OEt2, CH3CN/CHCl3, 0˚C; (c) TFA, r.t.;
(d) p-nitrophenyl chloroformate, pyridine, rt; (e) Pd(OH)2/H2, MeOH, rt.

To assess the in vitro potency of SGLT1 and SGLT2 inhibition, the inhibitory activities of the
compounds on SGLTs were determined using a cell-based assay in which the inhibition of the rate of
glucose uptake was monitored using CHO-K1 cells expressing human SGLT1 and SGLT2.
The inhibitory activities of SGLT1 and SGLT2 together with the topological PSA (TPSA)17 are listed
in Table 1.
A number of physicochemical property-based rules for oral bioavailability were evaluated.
Veber et al. proposed that a polar surface area (PSA) equal to or less than 140 Å2 (or 12 or fewer
H-bond donors and acceptors) is likely to have a high probability of good oral bioavailability in
rats.18 Tian et al. proposed that two simple parameters (PSA < 160 Å2 and log P > -2.2) were well
correlated with intestinal absorption, but not bioavailability.19 Therefore, we designed compounds
with polar functional groups focusing on TPSA and the number of H-bond donors and acceptors.
The inhibitory activities of SGLT1 and SGLT2 were significantly improved by incorporating
the methyl group on R2 4b, compared with our previously reported 4a. The substitution of R1 by
hydroxyl group 4c enhanced the SGLT1 and SGLT2 inhibition activities by several-fold, compared
with 4a. Then, we evaluated the SAR of the para position on the B ring (R3) by preparing
compounds 14a-14e with substitutions of low alky and alkoxy groups on R3. Compounds 14d and
14e had slightly more potent SGLT1 inhibitory activities than those of 14a and 14b, suggesting that
a linear alkyl group had some enhancing effect on the activity. The derivative 14d created by
introducing a methyl group had an SGLT1 inhibitory activity of 25 nM and an SGLT2 inhibitory
activity of 2 nM, with a TPSA value of 126 and 11 H-bond donors and acceptors. Since the
physicochemical properties of 14d were similar to those of the selective SGLT2 inhibitor
luseogliflozin, 14d was expected to exhibit good intestinal absorption. To acquire a low-absorbable
compound, we performed further optimization synthesis with the aim of increasing the TPSA and the
number of H-bond donors and acceptors.
Table 1
Structure-activity/TPSA relationships of C-phenyl 1-thio-D-glucitol derivatives
hSGLT1a
IC50 (nM)
26100c
671c
hSGLT2a
IC50 (nM)
73.6
Cpd.
R1
R2
R3
TPSAb
4a
4b
4c
H
H
H
Me
H
OEt
OEt
OEt
115
115
136
2.29
OH
4040c
17.4

14a
14b
14c
14d
14e
OH
OH
OH
OH
OH
Me
Me
Me
Me
Me
OEt
OMe
OiPr
Me
162
65
3
NTd
3
136
136
136
126
126
414
25
32c
2
Et
2
a IC50 values for hSGLT1 and hSGLT2 activities represent the mean values of at least two
experiments.
b The TPSA value was calculated using software from ACD/ Percepta, version 2015, Advanced
Chemistry Development, Inc.
c 0.1 mM methyl-α-D-glucopyranoside containing [14C] methyl-α-D-glucopyranoside.
d Not tested.
We anticipated obtaining a low absorbable compound by introducing an alkyl chain with a
water-soluble functional group on R3. Compounds 22c, 22d and 22e, in which a highly water-soluble
amide were introduced into a linear alkyl linker, achieved an increase in TPSA and the number of
H-bond donors and acceptors while maintaining the activity (Table 2). For future mass production,
we next confirmed the tolerability of a glucose structure instead of a 5-thio-glucose structure, for
which intermediate 11 has a 14-step synthesis from D-glucurono-3,6-lactone. As a result, the SGLT1
inhibitory activities of amide derivatives 22f, 22g and 22h were equivalent to those of 22c, 22d and
22e, respectively. In addition, the urea derivatives 25b and 25c showed slightly weaker SGLT1
inhibitory activities. Also, 25a with basic methylpiperazine exhibited a significantly weakened
SGLT1 inhibitory activity. Next, urea derivatives 30a and 30b, in which one carbon chain was
shortened, were obtained; these compounds had the same inhibitory activities as the amide
derivatives. Compound 30b showed strong inhibitory activities, with an SGLT1 inhibitory activity of
28 nM and an SGLT2 inhibitory activity of 7 nM, a TPSA value of 212, and 22 H-bond donors and
acceptors.
Table 2
Structure-activity/TPSA relationships of R4 on B ring
hSGLT1a
IC50 (nM)
hSGLT2a
IC50 (nM)
Cpd.
X
R4
TPSAb

22c
22d
22e
22f
22g
S
S
22
35
47
32
35
5
9
196
216
199
180
200
S
4
O
O
NTc
NTc
22h
25a
25b
25c
30a
O
O
O
O
O
51
764
65
7
5
5
7
4
183
146
172
212
172
175
51
30b
O
28
7
212
a IC50 values for hSGLT1 and hSGLT2 activities represent the mean values of at least two
experiments.
b The TPSA value was calculated using software from ACD/ Percepta, version 2015, Advanced
Chemistry Development, Inc.

c Not tested.
Given the promising good potency and low absorbability, we evaluated the pharmacokinetic
(PK) profile of compound 30b (TP0438836) in SD rats and the membrane permeability of
compound 30b using parallel artificial membrane permeability assays (PAMPA). The resulting PK
parameters and permeability of 30b are shown in Table 3. The total clearance (CLtotal), volume of
distribution at steady state (Vdss), and elimination half-life (t1/2) after the single intravenous
administration of compound 30b (2 mg/kg) were 1080 mL/h/kg, 439 mL/kg, and 0.362 hours,
respectively. As expected, compound 30b exhibited a low membrane permeability (0.3 × 10-6 cm/s).
Also, the bioavailability of compound 30b was very low in vivo. The maximum concentration (Cmax
)
after the oral administration of compound 30b (1 mg/kg) was 1.46 ng/mL, and the bioavailability (F)
was 0.05%. These data indicated that compound 30b had a low absorbability.
Table 3
Pharmacokinetic parameters in SD rats and permeability of 30b
Pharmacokinetic parameters
IV (2 mg/kg)a PO (1 mg/kg)b
Vdss
(mL/h/kg) (mL/kg)
1080 439
Permeability
PAMPA
at pH7.4
(× 10-6 cm/s)
0.3
Compound
CLtotal
t1/2
(h)
Cmax
(ng/mL)
1.46
Tmax
(h)
F
(%)
0.05
0.362
0.25
30b
a Dosing vehicle: saline
b Dosing vehicle: 0.5% CMC Na
The PK parameters were calculated using the mean value of the plasma concentration in three animals at
each point.
Next, the glucose-lowering effect of 30b was evaluated using an oral glucose tolerance test
(oGTT) in SD rats. Compound 30b was orally administered just prior to glucose loading, and the
plasma glucose concentration was then measured over 2 h. The reductions in glucose excursion
compared with vehicle administration (ΔAUC from 0 to 2 h) were 31.5%, 58.5% and 62.2% at 0.1,
0.3 and 1 mg/kg, respectively (Figure 2). Thus, the glucose-lowering effect increased in a
dose-dependent manner.
Moreover, we confirmed the absence of urinary glucose excretion after repeated dosing of
30b for 4 days at doses of 0.1 or 0.3 mg/kg twice a day, followed by subcutaneous glucose
administration on day 5. However, slightly urinary glucose excretions were observed at a dose of 1

mg/kg twice a day, but the value was not significant compared with the vehicle control.
Together, these results suggest that compound 30b exerted its hypoglycemic effect through
the inhibition of SGLT1 only in the gastrointestinal tract when administered at doses of 0.1 and 0.3
mg/kg. On the other hand, administration at a dose of 1 mg/kg twice a day in the high-dose group
might have resulted in some absorption of 30b, which most likely inhibited the activity of SGLT2 in
the renal tubules.
Figure 2. Effects of oral administration of 30b (0.03, 0.1, 0.3, or 1 mg/kg) on plasma glucose during
an oGTT in SD rats. Each point represents the mean ± SE. **P < 0.01, ***P < 0.001 vs. Vehicle
group, Dunnett’s test.(n=8)
In summary, a new series of C-phenyl D-glucitol derivatives was designed, synthesized and
evaluated for their SGLT1 inhibitory potency and low absorption. To achieve low absorption in this
new series, we performed an optimization study based on a strategy to increase the TPSA. The
optimization study led to the identification of compound 30b, which possessed the targeted PK
properties (low bioavailability) in SD rats and exhibited a glucose-lowering effect at a dose of 0.1
mg/kg (p.o.) in SD rats, suggesting its potential for the treatment of T2DM. Further optimization of
30b aimed at improving its safety is ongoing and will be reported in due course.
Acknowledgements
The authors thank Yoshiki Fukasawa for helpful suggestions and the collection of the ADME data.
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・Novel C-phenyl D-glucitol derivatives were evaluated as SGLT1 inhibitor.
・The low absorption compounds were chosen based on TPSA.
・Compound 30b (TP0438836) exhibited a potential for the treatment of T2DM.