Novel indole-N-glucoside, TA-1887 As a sodium glucose cotransporter 2 inhibitor for treatment of type 2 diabetes

Article abstract of DOI:10.1021/ml400339b

Inhibition of the renal sodium glucose cotransporter (SGLT) increases urinary glucose excretion (UGE) and thus reduces blood glucose levels during hyperglycemia. To explore the potential of new antihyperglycemic agents, we synthesized and determined the h

Full text of DOI:10.1021/ml400339b

Letter
pubs.acs.org/acsmedchemlett
Novel Indole‑N‑glucoside, TA-1887 As a Sodium Glucose
Cotransporter 2 Inhibitor for Treatment of Type 2 Diabetes
Sumihiro Nomura,*,† Yasuo Yamamoto,† Yosuke Matsumura,† Kiyomi Ohba,† Shigeki Sakamaki,†
Hirotaka Kimata,‡ Keiko Nakayama,‡ Chiaki Kuriyama,‡ Yasuaki Matsushita,‡ Kiichiro Ueta,‡
and Minoru Tsuda-Tsukimoto§
‡
§
†Medicinal Chemistry Research Laboratories, Pharmacology Research Laboratories, and DMPK Research Laboratories,
Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan
S
* Supporting Information
ABSTRACT: Inhibition of the renal sodium glucose cotransporter (SGLT)
increases urinary glucose excretion (UGE) and thus reduces blood glucose
levels during hyperglycemia. To explore the potential of new antihypergly-
cemic agents, we synthesized and determined the human SGLT2 (hSGLT2)
inhibitory potential of novel substituted 3-benzylindole-N-glucosides 6.
Optimization of 6 resulted in the discovery of 3-(4-cyclopropylbenzyl)-4-
fluoroindole-N-glucoside 6a-4 (TA-1887), a highly potent and selective
hSGLT2 inhibitor, with pronounced antihyperglycemic effects in high-fat
diet-fed KK (HF-KK) mice. Our results suggest the potential of indole-N-
glucosides as novel antihyperglycemic agents through inhibition of renal
SGLT2.
KEYWORDS: Type 2 diabetes, sodium glucose cotransporter 2 inhibitor, urinary glucose excretion, indole-N-glucoside, TA-1887,
antihyperglycemic effect
Because SGLT2 inhibition lowers plasma glucose levels in an
insulin-independent manner, SGLT2 inhibitors would be
effective for various diabetic patients, including those with a
progressive loss of beta cell function. In addition, we may not
expect the occurrence of hypoglycemia, which is a major con-
cern for current therapies with insulin and sulfonylureas and
weight gain that is often observed with other classes of cur-
rently approved antihyperglycemic agents. Therefore, the iden-
tification of novel SGLT2 inhibitors has become a goal for
medicinal chemistry.9−13
SGLT2 inhibitors, including O-glucosides such as 1
(T-1095)6 and 2 (sergliflozin)14 and C-glucosides such as 3
(dapagliflozin)15 and 4 (canagliflozin)16 have been studied in
clinical trials for the treatment of type 2 diabetes (Figure 1).
C-Glucosides appear to be metabolically more stable than
O-glucosides. During the search for the SGLT inhibitory
activity of various N-glucosides, we found that a novel indole-
N-glucoside 5 (Figure 1) inhibits human SGLT2 (hSGLT2).17
Accordingly, we report the optimization and antihyper-
glycemic effects of the substituted 3-benzylindole-N-glucosides
6 (Figure 1).
n patients with type 2 diabetes, the goal of therapy is to
Istrictly control blood glucose levels within the normal range.
Many agents for the treatment of type 2 diabetes improve
insulin secretion or insulin sensitivity; i.e., those are insulin-
dependent agents. Treatment with these agents is often
accompanied by the adverse events of hypoglycemia and
weight gain, and the therapeutic effect was found to be
attenuated along with a loss of pancreatic beta cell function in
some years.1
Recently, the inhibition of renal glucose reabsorption has
been studied as a novel method for controlling blood glucose
levels in patients with type 2 diabetes. Plasma glucose filtered in
the glomerulus is mainly reabsorbed by the sodium glucose
cotransporter 2 (SGLT2), which is located in the early proximal
tubules in the kidney.2−4 Under hyperglycemic conditions, the
reabsorption process is saturated and urinary glucose excretion
(UGE) increases linearly.5 The inhibition of renal glucose
reabsorption by an SGLT2 inhibitor 1 (T-1095, Figure 1)
enhances UGE and consequently lowers blood glucose levels in
diabetic animal models independently of insulin-action.6,7
Although SGLT1, which also functions to reabsorb glucose in
the distal segment of the proximal tubules, is expressed in the
intestine, heart, and trachea, SGLT2 is expressed exclusively in
the kidney.8 Extensive inhibition of SGLT1 could be
accompanied by undesired gastrointestinal effects. Therefore,
selective inhibition of SGLT2, rather than nonselective inhi-
bition of both SGLT1 and SGLT2, would be desirable for
antidiabetic agents.
We describe herein the syntheses of 3-benzylindole-N-
glucosides 6 according to the route outlined in Scheme 1.
Indolines 7 were N-glucosylated with D-glucose, followed by
Received: September 3, 2013
Accepted: November 13, 2013
Published: November 13, 2013
© 2013 American Chemical Society
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Figure 1. Structures of some O-, C-, and N-glucosides.
acetylation of the hydroxyl groups of the glucose moiety with
acetic anhydride and pyridine to provide indoline-tetra-O-
acetyl-N-glucosides 8. The stereochemistry of 8 was deter-
mined as the β-configuration by the coupling constant between
Table 1. SAR of Representative Substituted 3-Benzylindole-
N-glucosides
1
anomeric C−H and adjacent C−H (J = 9.3 Hz) in the H
NMR spectrum. Indolines 8 were oxidized by 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone in 1,4-dioxane and water to indoles
9.18 Following this, Friedel−Crafts acylation of 9 with para-
substituted benzoyl chlorides19 and aluminum trichloride
formed the corresponding 3-benzoylindole-N-glucosides 10.
The ketone group was sequentially reduced with sodium
borohydride in the presence of cerium(III) chloride20 and with
triethylsilane and boron trifluoride diethyl etherate to convert
10 to 3-benzylindole-tetra-O-acetyl-N-glucosides 11. Partially
deacetylated 11a-1 was then acetylated with a small amount
of acetic anhydride. Compounds 11 were also prepared by an
alternative route. Vilsmeier formylation of 9 with N,N-
dimethyformamide and phosphorus(III) oxychloride afforded
3-formylindoles 12. To generate 11, 3-formylindoles 12 were
coupled with 2 equivalents of aryl magnesium bromide21 in
tetrahydrofuran at 0 °C, followed by the reduction of the
resulting carbinols with triethylsilane. Finally, 3-benzylindole-
N-glucosides 6 were obtained by the deacetylation of 11 using
catalytic sodium methoxide in methanol and tetrahydrofuran.
We evaluated the effects of 3-benzylindole-N-glucosides 5
and 6 (Figure 1) on hSGLT2 activity and on UGE in male
Sprague−Dawley (SD) rats. The structure−activity relation-
ships (SARs) of the representative compounds are shown in
Table 1. Initially, we determined the effects of R1 substitution in
R2-ethyl derivatives 5. The substitution of R1 with a lower alkyl
(methyl) group (6b-1) resulted in potent hSGLT2 inhibition,
whereas substitution with a halogeno (fluoro) group (6a-1)
increased UGE. Thus, the effect of R2-substitution in R1-fluoro
derivatives was determined. The introduction of an alkyl (ethyl,
6a-1) or alkoxy (ethoxy, 6a-2) group as R2-substituents pro-
vided higher in vitro potency than that of a halogeno (chloro,
6a-3) group. Because the R2-cyclopropyl derivative 6b-4
showed high potency both in vitro and in vivo, further opti-
mization of cycloalkyl derivatives 6 was performed (Table 2).
We found that the cyclopropyl derivatives 6a-4 and 6c-4
a
Values are means of duplicate determinations (N = 1) unless
b
indicated otherwise. Each compound was orally administered at a
dose of 30 mg/kg to male Sprague−Dawley (SD) rats. Urinary glucose
excretion (UGE) data over a 24 h period were normalized per 200 g of
body weight (BW). Values represent the mean SEM (N = 3). N.D.:
not determined.
c
were more potent inhibitors of hSGLT2 than the 4- and
5-membered ring derivatives 6c-5, 6c-6, and 6a-6. Extensive
UGE was induced by 6a-4 and 6c-4, similar to 6b-4. While
these cycloalkyl derivatives were potent SGLT2 inhibitors,
R1-unsubstituted 6c-4 seemed to be chemically unstable, similar
to R1-unsubstituted 5 (data not shown).
Subsequently, we determined the selectivity of the highly
active compounds among glucose transporters. hSGLT1 or
hSGLT2 was stably expressed in Chinese hamster ovary-K
(CHOK) cells, and the inhibitory effects of 6a-1, 6a-4, and
6b-4 were investigated on the uptake of [14C]α-methyl-D-
glucopyranoside (AMG).22 The IC50 values of 6a-1, 6a-4, and
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a
Scheme 1. Synthesis of 6
a
Reagents and conditions: (a) D-glucose, EtOH−H2O, reflux; (b) Ac2O, pyridine, cat DMAP, CHCl3, rt; (c) DDQ, 1,4-dioxane−H2O, rt; (d)
ArCOCl, AlCl3, CH2Cl2, 0 °C; (e) NaBH4, CeCl3·5H2O, EtOH−THF, 0 °C; (f) Et3SiH, BF3·OEt2, CH3CN−CH2Cl2, −10 °C; (g) cat NaOMe,
MeOH−THF, rt; (h) DMF, POCl3, DCE, 70 °C; (i) ArMgBr, THF, 0 °C.
6b-4 were 210, 230, and 22 nM for hSGLT1, respectively, and
5.2, 1.4, and 1.6 nM for hSGLT2, respectively. Therefore, the
ratios of IC50 (SGLT1)/IC50 (SGLT2) for 6a-1, 6a-4, and 6b-4
were 40.4, 164.3, and 13.8, respectively. The effect of these
compounds on the facilitated glucose transporter 1 (GLUT1)
was determined using the incorporation of [3H]2-deoxy-D-
glucose (2-DG) in L6 myoblast cells.23 These compounds did
not inhibit GLUT1 activity at 10 μM in L6 myoblast cells.
Because selective inhibition of SGLT2, rather than nonselective
inhibition of both SGLT1 and SGLT2, would be desirable as
described above, compound 6a-4 (TA-1887/JNJ-39933673)
was selected as a clinical candidate.
studies demonstrated that oral dosing resulted in plasma
levels of 6a-4 that were sufficient to inhibit SGLT2.
C-Glucosides are metabolically more stable than O-glucosides.16
The N-glucoside part of 6a-4 was not hydrolyzed to its aglycon
in human and animal intestinal microsomes in vitro.24 This
indicates that the C−N bond of indole-N-glucosides is
metabolically stable in the presence of intestinal β-glucosidase,
similar to the corresponding C−C bond of C-glucosides. We
suggest that 6a-4 induces extensive UGE through continuous
suppression of renal glucose reuptake that is supported by
excellent pharmacokinetic properties as well as high potency of
SGLT2 inhibition.
Oral administration of 6a-4 at 30 mg/kg to male SD rats
induced glucose excretion over a 24 h period of 2502 mg per
200 g body weight, which is comparable to UGE induced by
C-glucosides.16 Pharmacokinetic studies showed elevated plas-
ma levels of 6a-4 following oral administration (Table 3). In
male SD rats, AUC0−inf,po, t1/2, and oral bioavailability were 28 169
ng·h/mL, 3.9 h, and 78%, respectively. Thus, pharmacokinetic
Single oral administration of 6a-4 at 3 mg/kg continuously
reduced blood glucose levels without influencing food intake in
hyperglycemic high-fat diet-fed KK (HF-KK) mice (Figure 2).
Analysis of AUC0−24 h of blood glucose levels revealed a 50%
reduction in 6a-4-treated animals compared with the vehicle-
treated group. Moreover, we observed a 50% reduction in
blood glucose level versus vehicle at 24 h. These data indicate
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Table 2. SAR of 3-(4-Cycloalkylbenzyl)indole-N-glucosides
Table 3. Pharmacokinetic (PK) Parameters of 6a-4 in Male
Sprague−Dawley (SD) Rats Following Intravenous and Oral
Administrations
compd
6a-4
6a-4
10
dose (mg/kg)
route
3
iv
po
Cmax (ng/mL)
tmax (h)
2723
1.5
AUC0−inf (ng·h/mL)
t1/2 (h)
10893
3.9
28169
3.9
CLtot (mL/h/kg)
Vdss (mL/kg)
F (%)
278
1147
78
those of O- and C-glucoside SGLT2 inhibitors. The optimized
compound 6a-4 (TA-1887), a highly potent and selective
inhibitor of hSGLT2 with favorable pharmacokinetic profiles,
remarkably increases UGE. In addition, oral administration of
6a-4 induced antihyperglycemic effects in HF-KK mice. We
conclude that these indole-N-glucosides have potential as a
novel chemical class of SGLT2-selective inhibitors for the
treatment of type 2 diabetes. Together with the recent
disclosure of indole-N-xylosides,25 N-glucosides would provide
a structural diversity of new SGLT inhibitors.
a
Values are means of duplicate determinations (N = 1) unless
b
c
indicated otherwise. N = 3. Each compound was orally administered
at a dose of 30 mg/kg to male Sprague−Dawley (SD) rats. Urinary
glucose excretion (UGE) data over a 24 h period were normalized
per 200 g of body weight (BW). Values represent the mean SEM
ASSOCIATED CONTENT
* Supporting Information
■
S
d
(N = 3). N.D.: not determined.
Description of in vitro hSGLT1, hSGLT2, and GLUT1 assays
and in vivo urinary glucose excretion and blood glucose-
lowering studies; detailed synthetic procedure for 6a-1, 6a-2,
6a-3, 6b-1, 6b-4, 6c-4, 6a-4, 6c-5, 6c-6, and 6a-6; HPLC
analysis of 6a-4. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*(S.N.) Phone: +81-48-433-2511. Fax: +81-48-433-2611.
E-mail: nomura.sumihiro@mw.mt-pharma.co.jp.
■
Notes
The authors declare no competing financial interest.
ABBREVIATIONS
■
SGLT, sodium glucose cotransporter; UGE, urinary glucose
excretion; SD rat, Sprague−Dawley rat; SAR, structure−activity
relationship; CHOK, Chinese hamster ovary-K; AMG, α-methyl-
D-glucopyranoside; GLUT, facilitated glucose transporter; 2-DG,
2-deoxy-D-glucose; HF-KK, high-fat diet-fed KK
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