Expert Opinion on Therapeutic Patents

ISSN: 1354-3776 (Print) 1744-7674 (Online) Journal homepage: http://www.tandfonline.com/loi/ietp20

Evolution of sodium glucose co-transporter 2

inhibitors as anti-diabetic agents
William N Washburn
To cite this article: William N Washburn (2009) Evolution of sodium glucose co-transporter 2
inhibitors as anti-diabetic agents, Expert Opinion on Therapeutic Patents, 19:11, 1485-1499
To link to this article: http://dx.doi.org/10.1517/13543770903337828

Published online: 26 Oct 2009.

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Review

Evolution of sodium glucose

co-transporter 2 inhibitors as
anti-diabetic agents
1. Introduction

William N Washburn

2. Patent review

Metabolic Diseases Chemistry, Research and Development, Bristol-Myers Squibb Co., P.O. Box5400,
Princeton, NJ 08543, USA

3. Conclusion

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4. Expert opinion

Background: A critical factor for maintenance of glucose balance is the renal

recovery of glucose from the glomerular filtrate mediated primarily by
sodium glucose co-transporter 2 (SGLT2). This capacity can be modulated by
SGLT2 inhibitors thereby providing a unique insulin independent method of
treatment of diabetes. Objective/method: A discussion of the evolution of
SGLT inhibitors as inferred from patents published from 2005 to 2009 is
prefaced by a brief review of the role of SGLT in glucose transport and the
clinical findings illustrating the therapeutic potential of SGLT inhibitors as
anti-diabetic agents. These compounds comprise O, C and N-glycosides
generated by attachment of an appropriate lipophilic aglycone component
to a suitable glucose analogue. Conclusion: The realization that the invivo
potency of O-glucosides was markedly less than that of C-glucosides necessitated a shift in medicinal chemistry focus of the pharmaceutical companies
pursuing SGLT2 inhibitors. Particular emphasis is placed on the strategy that
each used to circumvent the constraints imposed by prior art while utilizing
a common pharmacophore. The role of SGLT2 inhibitors for treatment of
diabetes will be established by the outcome of the five compounds in
advanced clinicaltrials.
Keywords: canagliflozin, C-glucoside, C-glycoside, dapagliflozin, phlorizin, remogliflozin,
sergliflozin, SGLT, SGLT2, type2 diabetes
Expert Opin. Ther. Patents (2009) 19(11):1485-1499

1. Introduction
1.1 Role

of thekidney

The mammalian kidney plays an essential role in the maintenance of glucose balance.
As the blood circulates through the kidneys, water, glucose and other low molecular
mass ions and molecules, not bound to the serum proteins, pass through the glomerular membranes to form the glomerular filtrate. During the descent of glomerular
filtrate through the proximal and distal tubules to the common collecting duct,
valuable components are recovered by transporters positioned along the luminal
surface. Two sodium glucose co-transporters, SGLT1 and SGLT2, enable the kidneys
of a normal healthy human with an average blood glucose level of 100 mg/dl to
filter and recover glucose from the glomerular filtrate at a rate of 0.125 g/min
or 180 g/day [1,2]. As a consequence, negligible amounts of glucose appear in the
urine [3,4].
The rate of glucose filtration for healthy individuals increases proportionally as
the glycemic level increases. As illustrated in Figure1, the recovery rate of glucose
matches the filtration rate for glycemic levels up to 200 mg/dl, the threshold
glycemic level. At this point, the glucose concentration in the glomerular filtrate
equals the finite recovery capacity of the kidney and so the recovery rate cannot further
increase above the maximal reabsorptive capacity of the proximal tubule (Tm)

10.1517/13543770903337828 2009 Informa UK Ltd ISSN 1354-3776

All rights reserved: reproduction in whole or in part not permitted

1485

Rate of glucose
filtration/reabsorption/excretion
(mg/min)

Evolution of sodium glucose co-transporter 2 inhibitors as anti-diabetic agents

600

Filtered

Excreted

400

Reabsorbed

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1.2 Ameliorative

role of SGLT2 inhibitors for

type2diabetes
200

Tm
Threshold

200
600
400
Plasma glucose (mg/dL)

800

Figure 1. Glucose filtration, recovery and excretion by the

kidney of a non-diabetic individual [98].

value. The maximum renal recovery capacity provided by

these transporters is such that upward of 360 g/day of glucose
can be recovered before glucose excretion in urine occurs. Any
additional increase in glycemic levels results in a progressively
greater mismatch between glucose filtration and recovery rates
resulting in ever increasing levels of glucose appearing in the
urine. The rate of glucose excretion increases linearly as the
blood glucose concentration becomes evermore elevated.
The SGLT2 transporter, thought to be the major contributor to renal glucose reabsorption, is localized on the luminal
surface of the S1 segment of the proximal tubules immediately
downstream of the glomeruli [2]. The SGLT1 transporter is
found similarly sited on the S3 segment. Both transporters
couple transport of glucose with that of Na+ thereby utilizing
the free energy gain from transport of Na+ down a concentration gradient to compensate for transport of glucose against
the gradient. ATP-dependent Na+/K+ pumps maintain the
prerequisite low intracellular Na+ concentrations within the
endothelial cells forming the tubule wall. Recovered glucose
is subsequently exported to the blood stream by the facilitative GLUT1 and GLUT2 transporters. The SGLT2 transporter is a low affinity/high capacity glucose transporter that
co-transports glucose and Na+ in a 1:1 ratio, whereas SGLT1
is a high affinity/low capacity transporter that co-transports
glucose and Na+ in a 1:2 ratio [5].
The SGLT2 transporter appears to be expressed exclusively
in the human kidney whereas SGLT1 is expressed primarily
in the small intestine, heart and kidney [6-8]. In addition,
low level SGLT1 expression has been reported for other tissues.
Humans lacking a functional SGLT2 gene (type O familial
glucosuria) appear to live normal lives other than exhibiting
copious glucose excretion (as much as 140 g/day) with no
adverse effects on carbohydrate metabolism [9]. In contrast,
individuals bearing a SGLT1 gene mutation experience
glucosegalactose malsorption reflecting the essential role of
SGLT1 in the transport of glucose and galactose across the wall
of the small intestine [5]. Given the predominant role of SGLT2
for renal glucose recovery as well as the relatively benign
1486

phenotype presented by humans bearing SGLT2 mutations,

most pharmaceutical efforts have focused on devising inhibitors
selective for the SGLT2 transporter.

The hallmarks of type 2 diabetes are -cell dysfunction

manifested initially as delayed first phase insulin release and
peripheral insulin resistance that gives rise to progressively
increasing hyperglycemia. Hyperglycemia, abetted by other
metabolic derangements, is the major contributor to the
onset of the microvascular and macrovascular complications
associated with type 2 diabetes [10]. Chronically elevated
glycemic levels can result in higher protein glycation, reduced
insulin secretion, -cell exhaustion resulting in apoptosis,
increased oxidative stress and heightened insulin resistance [11].
The consequences of these metabolic changes are manifested
by diminished wound healing as well as tissue damage of the
retina, nerves and kidney that give rise to increased incidence
of gangrene, retinopathy, neuropathy and nephropathy
resulting in amputations of extremities, blindness, renal failure,
cardiovascular disease and stroke [12,13].
Inhibition of the SGLT2 transporter represents a noninsulin dependent mechanism to reduce glycemic levels.
Progressive inhibition of the SGLT2 transporter is manifested
by a dose-dependent lowering of Tm resulting in a left shift
of the threshold value. As a consequence, glucose excretion
in urine occurs at progressively lower glycemic concentrations.
Dependent on the new Tm value achieved and the glycemic
level of the patient, glucose excretion would occur either
intermittently during postprandial glucose excursions or during
both fasting and fed conditions. Ideally, the resultant reduction
in blood glucose levels would result in a reduction in hepatic
insulin resistance. As the liver became more insulin responsive,
hepatic glucose output would decline. The resultant decrease
in glycemic levels would reduce both peripheral insulin resistance and demands on pancreatic cells resulting in a progressive shift to more normal glucose balance. A further benefit
is that the caloric expenditure arising from glucose excretion
would induce weight loss. Because this mechanism does not
depend on insulin, in principle SGLT2 inhibitors could be
combined with all other anti-diabetic agents with minimal
risk of increased incidence of hypoglycemia.
1.3 Modulation

ofSGLT2

Renal glucose reabsorption has been inhibited by a variety

of SGLT2 inhibitors of which the preponderance from
structural considerations appear to be competitive glucoside
inhibitors [14,15]. These invariably contain a glucose derivative
attached to a hydrophobic aglycone typically containing several
aryl rings. Prior to 2005, applications predominantly featured
novel O-glucosides as SGLT2 inhibitors (Figure2); however,
in the last few years the primary focus has been inhibitors
containing a C-glucoside linkage. The structures disclosed in a
few applications (see section 2.4.1) suggest a totally different

Expert Opin. Ther. Patents (2009) 19(11)

Washburn

OH

HO

OH

Me

OH

HN

OCH3

N
O

OH

OH

RO
HO

OH

RO
OH

RO

OH

OH

OH
OH

OH

OH

OH

2a R = H T-1095
2b R = OCOMe T-1095

1
O

OH

OH

OH

3a R = H Sergliflozin A
3b R = OCOEt Sergliflozin

4a R = H
4b R = OCOEt
Cl

Et
O

MeO

MeO

OH

OH
O

OH

OH
HO

HO
OH

RO
OH

HO
OH

OH

OH

OH

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Et

O
OH

OH

5a R = H
5b R = OCOMe

Cl

8
Dapagliflozin

Y
Et
OH

OH

O
HO

HO

OH

OH
OH

OH

Figure2. SGLT2 inhibitors predating 2005.

SGLT2: Sodium glucose co-transporter2.

mode of inhibition because these entities do not contain a

glucose component; however, these applications did not address
whether the inhibitory response arose from competitive or
allostericmodulation.
The natural product phlorizin 1 has been a well-known
glucosuric agent for > 100years prior to the elucidation of the
mode of action of this phenolic O-glucoside [16]. Systematic
design of SGT2 inhibitors began with identification of the
SGLT2 transporter and the realization of its potential as a
molecular target. The initial efforts at Tanabe Seiyaku entailing modification of phlorizin culminated in the discovery of
T-1095A 2a [17-19]. The pharmacological promise conveyed
by the in vivo activity of the methyl carbonate pro-drug
T-1095 2b and analogues galvanized the inception of similar
programs at a number of companies. These efforts focusing
initially on defining alternative modes for presentation of
the hydrophobic aglycone while maintaining high inherent
SGLT2 affinity and selectivity versus SGLT1 led to a number
of applications from Kissei and Bristol-Myers Squibb during
2000 2003 describing o-benzyl phenolic O-glucosides such
as 3a and 5-benzyl pyrazolone O-glucosides 4a [20-22]. Subsequent applications from other groups reported the successful
utilization of heteroaryl aglycone components or modification
of the glucose moiety [14]. It was widely recognized that the

susceptibility of O-glucosides to glucosidase degradation

impacted bioavailability and duration of action. Pro-drugs,
specifically lower alkyl carbonates of the C6 hydroxyl, improved
oral bioavailability by prevention of cleavage in the gut;
however, after absorption of the pro-drug and subsequent
release by esterases, the active agent became subject to
hydrolysis by glucosidases in a variety oftissues.
In 2001, two independent patent applications from Kotobuki
and Bristol-Myers Squibb describing C-aryl glucosides were
published. Kotobuki disclosed analogues of T-1095A for
which meta substitution of the central aryl ring was the predominant mode of attachment of the glucose moiety and the
tethered distal aryl ring rather than the characteristic ortho
attachment of O-glucosides [23]. Although no in vitro data
pertaining to SGLT2 inhibition were shown, the in vivo
profile was encouraging despite modest invivo potency. When
administered intraperitoneal to 6 week old Sprague-Dawley
(SD) rats at 10 mg/kg twice over an 8 h interval, the 24 h
glucose excretion response induced by the meta isomer 5a
(241 mg of glucose) was 60-fold greater than that of the ortho
isomer 6 (4 mg of glucose). Moreover, contrary to O-glucosides,
the glucose excretion response of the methyl carbonate 5b
(8.9 mg of glucose) was markedly less than that of 5a as
would be expected for hydrolytically stable C-glucosides.

Expert Opin. Ther. Patents (2009) 19(11)

1487

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Evolution of sodium glucose co-transporter 2 inhibitors as anti-diabetic agents

A series of applications from Bristol-Myers Squibb disclosing

that C-glucosides of meta substituted diarylmethanes and
especially featuring the preparation of multi-gram amounts
7, 8 and 9 ensured that the pharmaceutical industry became
aware of the finding that meta substituted C-aryl glucosides
generated potent SGLT2 inhibitors. In addition, the distribution of examples implied that substitution at 4 and 4 of the
two aryl rings with lipophilic substituents was preferred [24].
Subsequently in 2002, an application from Bristol-Myers
Squibb was published which indicated that crystalline complexes of these amorphous C-aryl glucosides could be obtained
with amino acids such as L-proline and L-phenylalanine [25,26].
Additional applications from Bristol-Myers Squibb published
in 2003 specifically claimed and detailed the preparation of
a single compound 8 [27,28]. These were followed by a selection
application which not only disclosed structure 9 but also
compared the relative abilities of 7, 8 and 9 to reduce glycemic
levels of diabetic streptozotocin treated SD rats when orally
administered at 0.1 mg/kg [29].
1.4 Dapagliflozin,

a casestudy

Dapagliflozin 8 is the only SGLT2 inhibitor for which

extensive clinical data have been disclosed. The EC50 for
hSGLT2 is 1.1 nM; selectivity versus hSGLT1 is 1200 [30].
Potency and selectivity is somewhat diminished versus the
corresponding rat SGLT transporters; rSGLT2 EC50 is 3nM
with a selectivity of 620-fold versus rSGLT1. The preclinical
pharmacological profile exhibited by dapagliflozin was very
promising [31]. When administered orally to normal SD rats,
dose-dependent glucose excretion ensued; doses of 1 and
10 mg/kg produced 1000 and 1900 mg/200 g body weight,
respectively, over 24h. When administered to diabetic ZDF
rats with fasting blood glucose levels of 350 mg/dl, dosedependent glucose excretion correlated with progressive reductions in glycemic levels such that near normalization was
achieved with 1 mg/kg at 6h post dose. Following subchronic
administration for 2weeks, plasma glucose levels of diabetic
ZDF rats not only were reduced during the study but also
an improvement in glucose production and utilization was
observed at 3days following completion of thestudy.
Clinical studies with dapagliflozin have been very
encouraging [32-34]. The PK profile is amenable to daily
administration; tmax is 1h; t1/2 in humans is 15h. When
administered to healthy volunteers, the 20mg dose produced
a maximum pharmacodynamic response resulting in 55 60g
of glucose being excreted in urine over 24 h. Higher doses
did not increase the glucosuric excretion response but rather
merely prolonged the duration of glucose excretion. Given
that for these individuals 180 g of glucose is filtered and
recovered daily and the total renal recovery capacity is at least
360g, excretion of 60g requires that dapagliflozin inhibited
a minimum of 67% of the total capacity. Glucose excretion was
immediate and sustained throughout the 2 week Phase IIA
study with type 2 diabetic patients resulting in a continual
improvement in fasting glucose levels and in postprandial
1488

glucose levels for the duration of the study. For these

individuals, the mean amount of glucose excreted over 24h
increased from 40 g following a 5 mg dose to 70 80 g
following a 25 mg dose. This apparently was the maximum
response as no further increase was observed with a 100mg
dose. When dapagliflozin was administered to type2 diabetics
in a Phase IIB 12 week study, dose related reduction in
HbA1C of 0.37 0.7% along with a modest body weight
reduction of 1.3 2.2% was achieved after placebo subtraction [35]. The most common adverse events were urinary tract
and genital infection, nausea, dizziness, headache, fatigue, back
pain and nasopharyngitis. Small increases in urine volume as
well as a 1.5 2.9% increase in hematocrit were noted. The
incidence of reported but unverified hypoglycemic events
was higher than placebo but similar to that of metformin,
an antihyperglycemic agent known to present little risk of
hypoglycemia. No clinically meaningful changes in serum
sodium, potassium or calcium levels were detected but serum
magnesium was elevated and phosphate was reduced.
Currently, PhaseIII studies are in progress withdapagliflozin.
2. Patentreview

Because SGLT2 applications published prior to 2005 have

been previously reviewed, this review focuses on subsequent
applications with particular emphasis on C-glucosides [14]. Most
groups utilized CHO-K1 cells which had been transfected with
hSGLT1 and hSGLT2 for invitro evaluation; the reader can
assume these cell lines were used unless otherwisestated.
2.1 C-glucosides

The above Bristol-Myers Squibb disclosures coupled with the

knowledge that Bristol-Myers Squibb was actively evaluating
SGLT2 inhibitors in the clinic did not go unnoticed. The
focus of the discovery efforts of most groups subsequently
shifted to C-aryl glucosides. Five notable teachings that could
be inferred from the Bristol-Myers Squibb applications were
preferential use of aglycones generated by linking two planar
benzenoid rings with a methano spacer, a meta spatial presentation of the glucoside and benzyl appendages of the
central aryl ring, the use of TMS protected gluconolactone
in the synthetic sequence to introduce the glucose moiety,
purification of the C-glucoside as the crystalline peracetate
to avoid extensive chromatography of an amorphous final
product and formation of complexes with amino acids to
convert the amorphous C-glucoside into a tractable crystalline
solid. These findings guided the efforts of other groups as they
sought to generate alternative proprietary C-glucoside based
SGLT2inhibitors.
In 2004, the first of many subsequent non-Bristol-Myers
Squibb C-aryl glucoside containing applications were published.
To obtain a proprietary position, these groups have used a
variety of strategies to modify the diarylmethane aglycone A
in order to circumvent the constraints imposed by the
Bristol-Myers Squibb applications. Some utilized substituents

Expert Opin. Ther. Patents (2009) 19(11)

Washburn

that were outside the Bristol-Myers Squibb applications; some

replaced one or both of the benzene rings with heteroaryls
as an isosteric phenyl equivalent; and others modified the
glucose moiety. In all instances, the spatial presentation
inherent in the original pharmacophore has been maintained:
a planar central ring substituted 1,3 with a glucose-like moiety
and a methano linked second planarring.

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2.1.1 Kotobuki/Astellas

In 2004, a joint application was published describing

C-glucosides for which the distal aryl ring of A had been
replaced with heterocycles, primarily benzothiophenes attached
at C2 [36] (Figure 3). In vivo activity was assessed by determining the percent reduction of the 8 h glucose AUC of fed
KK-Ay mice after oral administration at 1 mg/kg. Disclosed
IC50 values ranged from 3.8 to 21 nM for the predominately
benzothiophene containing compounds. Of these, 10 (3.8 nM)
reduced the 8h glucose AUC of fed KK-Ay mice 34% relative
to vehicle after oral administration. Among the compounds
disclosed without accompanying biological data was
compound 11. A subsequent application reported that the
1:1 complex of L-proline and 11 possessed excellent properties
amenable for incorporation in pharmaceuticals, exhibited an
SGLT2 IC50 of 8.4 nM and unspecified antihyperglycemic
activity in fed KK-Ay mice [37]. Also in 2004, a second joint
application disclosed a series in which the distal ring was an
azulene moiety attached predominately at C2 (IC50 ranging
5.7 99 nM) of which 12 (5.7 nM) and 13 (8.9 nM) are
representative [38]. Antihyperglycemic activity of 12 in the fed
KK-Ay mice model was 45% following oral administration
at 3 mg/kg. Compound 13 subsequently became the focus
of two patent applications, one devoted to the synthesis and
the other disclosing that a 1:1 choline complex exhibited
properties amenable for incorporation in pharmaceuticals [39,40].
Presumably, the above complexes of 11 and 13 correspond
to the Astellas clinical candidates ASP1941 and YM-543.

IC50 values for 14 and 16 suggests that the spatial presentation

of this second chemotype may be more conducive for high
affinity SGLT1 selective SGLT2 inhibitors. A third application
appearing in 2006 described the utilization of N- benzylated
indoles glucosylated at C3 as the central ring to generate a series
of compounds represented by 18 (6 nM IC50) and 19 [43].
The IC50 value for 18 suggests that this series appears to
contain potent SGLT2 inhibitors; however, selectivity versus
SGLT1 may be modest in light of an 83 nM SGLT1 IC50
disclosed for the 7-methyl isomer. In general, oral administration of this chemotype to 6week old SD rats at 1 mg/kg
induced a modest glucose excretion response (20 500 mg)
over 24 h per 200 g of body weight; however, a robust
response of > 1500 mg was obtained for a few compounds
such as 19.
2.1.3 Tanabe/Mitsubishi

In 2005, a broad application was published containing

examples for which the distal ring of A had been replaced
with predominately 2-benzothiophenes or 2-thiophenes substituted with aryls at C5 to generate inhibitors such as 20
(2.2 nM IC50) [44]. This series appears to generate quite
potent SGLT2 inhibitors as IC50 values ranged from 0.6 to
9.8 nM for the disclosed compounds. The glucose excretion
response over 24 h was 2000 mg of glucose following oral
administration of 20 and a number of other analogues at 30
mg/kg to 6week-old male SD rats. A subsequent application
in 2008 described preparation and properties of a crystalline
semi-hydrate of 20 amenable for incorporation in pharmaceuticals [45]. Advanced clinical trials are now proceeding
with 20, now named canagliflozin or TA-7284. A few
C-glucosides exemplified by 21 (31 nM IC50) and 22 (5 nM
IC50) have been disclosed in which the C6 or C4 hydroxyl of
the sugar moiety were respectively replaced with fluorine [46].
Oral administration of 22 at 30 mg/kg as previously described
produced a glucose excretion response in SD rats resulting in
the loss of > 2400mg ofglucose.

2.1.2 Kissei

Two applications were published in 2005; the central aryl ring

of the aglycone in both was predominantly a benzothiophene
moiety. In one application, the C2 glycosylated benzothiophenes were benzylated at either C4 or C7 to generate
compounds such as 14 (2 nM IC50) [41]. Elongation of the
tether appeared not to be beneficial as the IC50 values of C4
ethano linked 15 and its isomeric C7 linked counterpart were,
respectively, 58 and 130 nM. Selectivities versus SGLT1 for
methano linked counterparts of 14 were not disclosed; however, the ethano linked 15 exhibited only fourfold selectivity
for SGLT2. In the second application, C5 glycosylated
benzothiophenes were benzylated at C3 to generate compounds such as 16 (IC50 1.4 nM) [42]. Although the impact
of homologation of the spacer to generate 17 on SGLT2
affinity was not disclosed, a SGLT1 IC50 of 1500 nM was
reported. The sevenfold reduction in SGLT1 potency of 17
versus 15 in conjunction with essentially equivalent SGLT2

2.1.4 BoehringerIngelheim

The Boehringer Ingelheim group, capitalizing on the narrow

definition for substituents in the initial Bristol-Myers Squibb
C-glucoside application, focused primarily on the identification of alternative substituents attached to C4 or C4 of the
diarylmethane aglycone A. Despite the narrow scope of the
exemplified examples such as 23 and 24, the claims encompassed a large expanse of intellectual property[47]. These claims
have been bolstered by 11 subsequent applications that
exemplify aspects of the genus claimed in this original filing.
The use of an ethinyl substituent was extended to include
propargyl alcohol and ethers 25 or ethinyl linked heteroaromatics 26 [48]. Modifications of the glucose moiety itself were
explored as evidenced by a 2006 application disclosing
that SGLT2 inhibitors such as 27 were obtained following
replacement of the C5 glucose hydroxyl of a dapagliflozin
analogue with F, H or OMe [49].

Expert Opin. Ther. Patents (2009) 19(11)

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Evolution of sodium glucose co-transporter 2 inhibitors as anti-diabetic agents

OCH3

OCH3

HO

S
MeO

MeO

O
HO

HO

HO

O
HO

HO
HO

HO

OH

OH

HO

OH
OH

OH

OH

10

12

11

13

OH
O

O
HO

HO

OH

OH

OH
O

OH

OH

OH

HO

OH

OH

Et

HO

OH
OH

OH

OH

OH

14

15

16

17

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X
Cl

Cl
S

OH

OH
O

Me

S
O
O
HO

HO

OH

OH
HO
HO

OH

OH

OH

OH

OCH3

OH
OH

18 X = Me; Y = H
19 X = Cl; Y = Me

20

21
Cl

Cl

Cl

22

OH

OH

OH

OH
O

O
OCH3

HO

HO

OH
OH

23

OH

OH

OH

OH

OH

24

25

26
CN

Cl

Cl

HO

HO

OH

CN
MeO

Et

Et

Et

O
P

O
HO

HO

OH

OH

OH

OH

HO

HO

OH

OH
X

27

OH

OH

OH

OH

29

28
Cl

OH

30

Cl
F

Et

Et

HO
OH

OH
OH

31

HO

OH

OH

OH

O
HO

OH

OH

OH

OH
OH

OH

32

HO

33

34

Figure3. C-glucoside based SGLT2 inhibitors disclosed during 2005 2009 by Kotobuki/Astellas, Kissei, Tanabe/Mitsubishi
and Boehringer Ingelheim.
SGLT2: Sodium glucose co-transporter2.

1490

Expert Opin. Ther. Patents (2009) 19(11)

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Washburn

This extension of the Boehringer Ingelheim claims to a

wide variety of C5 glucose analogues appears not to have
been further pursued. In 2007, derivatives such as 28 were
disclosed for which the terminal carbon of ether and alkyl
substituents of the distal ring was substituted with a dialkylphosphinoyl moiety [50]. In 2007 and 2008, a series of patents
were published in which the substituents of the central aryl
ring of compound 9 were altered to obtain novelty. Replacement of chloro with cyano was exemplified by structures such
as 29 [51]. Subsequently, this approach was extended to include
benzonitriles 30 with an alkoxy substituent primarily at C5
but also at C6 [52]. Utilization of cycloalkoxy or cycloalkyl
substituents at C5 or C6 were reported for central aryl rings
bearing a methyl or chlorine at C4 [53]. In 2008, incorporation
of cycloalkyl substituents at C4 of the central aryl ring 31
was disclosed [54]. Finally in 2008, an application was published in which any two of the four open positions of the
distal ring were fluorinated to generate compounds such as
32 [55]. Assessment of the merits of these perturbations of
the dapagliflozin structure is not possible because no specific
biological data was disclosed in any of these Boehringer
Ingelheim applications. All include the statement that the
compounds of the invention may have IC50 values less than
1000nM, particularly less than 200nM, particularly preferably
less than 50 nM. No indication of selectivity versus SGLT1
or in vivo activity was provided. Despite the absence of any
biological data being reported, the profile of at least three
compounds are to be judged promising because three patent
applications were published each describing, respectively, the
generation and characterization of crystalline complexes of 24,
33 and 34 [56-58]. Presumably, one of these corresponds to BI
10773, a clinical candidate in Phase IIB clinical trials.
2.1.5 Taisho

In 2006, an application was published extending Taishos prior

use of O-5-thiaglucosides as an SGLT targeting vector to
generate 5-thiapyranosyl C-glucosides of diarylmethanes such
as 35, the thiaglucoside counterpart of dapagliflozin 8 [59]
(Figure 4). Comparison of the SGLT1 and SGLT2 IC50
values of 1200 and 80 nM, respectively, for 35 to the corresponding values of 1300 and 1.1 nM for 8 suggests that
replacement of the pyranosyl oxygen with a sulfur adversely
impacted SGLT2 potency (70x) whereas SGLT1 potency was
unperturbed. As a consequence, 35 exhibited only 15-fold
selectivity versus SGLT1. In general, members of this chemotype which were substituted at C4 and C4 exhibited SGLT2
IC50 values of 100nM with 10- to 20-fold selectivity versus
SGLT1. However, introduction of an additional methoxyl at
C6 of the central ring enhanced SGLT2 potency while reducing
that of SGLT1 with the result that compounds such as 36
(32 nM SGLT2 IC50) exhibited a 180-fold selectivity versus
SGLT1. A subsequent application taught that when small
lipophilic substituents were attached to C4 and C4 of 36,
replacement of the C6 methoxyl with hydroxyl enhanced
SGLT1 potency more so than SGLT2 [60]. For example, this

modification gave rise to non-selective potent SGLT1/2

inhibitors such as 37 (IC50 = 17 and 20nM for SGLT1 and
SGLT2, respectively). Oral administration of 37 at 1 mg/kg
to db/db mice reduced the 24h AUC for glucose by 48.5%.
Another application disclosed that potent orally active
non-selective inhibitors of SGLT1 and SGLT2 such as 38
(IC50 values = 11 and 17nM, respectively) could be obtained
upon replacement of the distal aryl C4 methyl of 37 with
hindered hydroxylated amides of -substituted propanoic,
butanoic and pentanoic carboxylic acids [61]. Oral administration of 38 at 1 mg/kg 5 min prior to a glucose solution
(2 g/kg) produced a 70% reduction in the 1h glucose AUC
of fasted 8 week-old male streptozotocin induced diabetic
SD rats. A similar pharmacological profile was obtained for
O-pyranosyl containing counterparts exemplified by 39, a
potent non-selective SGLT inhibitor for which the respective
SGLT1 and SGLT2 IC50 values of 11 and 17nM were identical to that of 38 [62]. Despite an identical in vitro profile,
when 39 was evaluated under the conditions described for
38, the 42% reduction in glucose AUC was only 60% of
that achieved with 38. However, in vivo potency could be
fully regained for this oxa pyranosyl series upon replacement
of the 4-butanamide substituent with alkyl ureas such as 40
(69% reduction in glucose AUC).
2.1.6 Chugai

This group explored a variety of approaches to generate novel

C-glucosides of aglycone A. In 2006, both aryl rings of A
were replaced with bicyclic aromatics to generate analogues
exemplified by 41 (18 nM SGLT2 IC50) [63]. Also in 2006,
an application was published describing a series of diarylmethane C-glucosides for which the pyranosyl oxygen was
replaced by a methylene thereby converting the glucose moiety
into perhydroxylated cyclohexanes such as 42, 43 and 44
(SGLT2 IC50 values of 7, 11 and 7nM, respectively) [64]. In
2006, the first of two Chugai applications described potent
C-glucosides arising from a novel structural modification of
aglycone A to generate 1,1-anhydro-2-hydroxymethyl
5-benzylphenylgluco-pyranoses 45 (IC50 4. nM) [65]. The
second application disclosed an extensive amount of invitro
structureactivity relationship (SAR) for both SGLT1 and
SGLT2 inhibition by analogues such as 46 (SGLT1 and
SGLT2 IC50 values of 425 and 1.5 nM, respectively) [66].
Despite the constraints imposed by the anhydro pyranose
structure, SGLT2 potency of 46 is comparable to its counterpart 8 but selectivity versus SGLT1 was diminished fourfold.
Oral administration of 46 at 0.3 mg/kg to 11week-old db/db
mice reduced blood glucose levels by 52 and 25% at 6 and
24h post dose, respectively, relative to that of controls. In a
further expansion of this approach, the central benzene ring
was replaced with a bicyclic heterocycle comprising indoles,
indazoles, benzisothiazole, benzisooxazole and benzthiophenes
to generate potent SGLT2 inhibitors exemplified by the
C3 benzylated benzthiophene 47 (3.9 nM IC50) which
exhibited comparable potency to that of its non-annelated

Expert Opin. Ther. Patents (2009) 19(11)

1491

Evolution of sodium glucose co-transporter 2 inhibitors as anti-diabetic agents

Cl

Cl

N
H
MeO

O
Et

OH

HO

OH

Et

OH

HO

HO

OH

HO

OH

OH

OH

OH

OH

OH

35

OH

36

37
HO

38

OH
OCH3

HO

HO

NH

NH
O

HN

HO

OH

HO

OH

HO
OH

OH

HO

OH

Et
OH

OH

HO

MeO

HO

HO
O

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OH

HO

OH

HO

OH

OH

OH

OH

39

41

40

42
Cl

Et

MeO

Et

MeO

Et
Et

HO

OH

OH

OH

O
HO

HO

OH

OH

Et

HO
OH

OH

OH

HO

HO

OH

OH
OH

OH

OH

OH

OH

43

44

45

46
Cl

Cl

Et

Et

47
Cl

(CH2)n

Et

Et

OH
S

OH

OH

OH
O

O
HO
OH

HO

HO

HO
OH

OH

OH

OH
OH

48

49

Cl

50 n = 1, 2, 3

Cl

Ac

S
O

HO

OH
OH

52

Et

HO

MeS

OH

OH
N

O
OH

Me

Et

HO

O
OH

51

Cl

O
OH

OH

OH

OH
OH

53

HO

OH
OH

54

55

Figure4. C-glucoside based SGLT2 inhibitors disclosed during 2005 2009 by Taisho, Chugai Selyaku Kabushiki, Theracos, Lexicon
and Jansen/Mitsubishi/Tanabe.
SGLT2: Sodium glucose co-transporter2.

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Expert Opin. Ther. Patents (2009) 19(11)

Downloaded by [Gazi University] at 07:12 12 February 2016

Washburn

counterpart 45 [67]. Also in 2008, an application was published disclosing thiapyranosyl analogues such as 48 (12 nM
SGLT2 IC50) [68]. Comparison of 48 with 45 suggests that
in this instance modification of the sugar moiety reduced
SGLT2 potency threefold. No in vivo data were disclosed for
analogues of 47 or 48.

inhibit the SGLT transporters in the small intestine and

kidney [75]. Although no in vivo data were provided, the
inference is that any beneficial anti-diabetic pharmacology due
to 55 must arise via inhibition of SGLT1 or some SGLT
transporter other than SGLT2 because the SGLT2 IC50 of 55
was reported to be 1100 nM.

2.1.7 Theracos

2.2 N-glucosides

In 2007, an application was published describing a series

of hexahydrospiroindenes represented by 49, analogues of
1,1-anhydro-2-hydroxymethyl 5-benzylphenylglucopyranoses
represented by 45 which overlapped with those previously
disclosed by Chugai as well as novel variants of 45 in which
the C6 hydroxyl was replaced with OCH2CF3 or NMe2 or
an acylated amine [69]. No meaningful SAR assessment is
possible for the SGLT2 IC50 data obtained with transfected
HEK293 cells because all three Theracos applications report
SGLT2 IC50 values to be < 1000nM. SGLT1 IC50 values for
analogues of 49 were reported to be > 10,000 nM. In 2008,
an application was published describing a series of ethers
obtained from modification of 9 entailing the introduction of
either a hydroxymethyl, 2-hydroxylethyl or 3-hydroxypropyl
substituent at C6 of the central aryl ring followed by alkylation to generate a series of ethers exemplified by the three
butynyl ethers 50 [70]. Also in 2008, an application was published disclosing tetrahydropyran analogues such as 51 of the
1,1-anhydro-2-hydroxymethyl 5-benzylphenylglucopyranoses
45 [71]. In 2009, an application was published disclosing
dapagliflozin analogues such as 52 substituted at C4 of the
distal ring with ethers or alkanes containing multiple functionality that avoid the constraints of the Bristol-Myers Squibb
and Boehringer Ingelheim applications [72]. Compound 52
appears to be of particular interest as a multi-hundred gram
synthesis was described as was the powder X-ray spectrum and
DSC scan of the 1:2 crystalline complex of 52 withproline.

2.2.1 TanabeSeiyaku

2.1.8 Lexicon

In 2008, an application was published disclosing a series of

compounds, for which 53 and 54 are representative, arising
from modification of the glucose moiety of dapagliflozin 8
entailing replacement of the glucosyl hydroxymethyl with
OH, lower alkoxy, SMe and SO2Me or replacement of the
pyranosyl oxygen with a acetylated nitrogen [73]. No biological
data were provided for specific compounds, although conditions
were described for both invitro evaluation of SGLT1/2 IC50
values using hSGLT1/2 transfected HEK293 cells and invivo
evaluation of the glucose excretion response of C57 albino
male mice. In 2009, publication of a patent application
describing the preparation of crystalline 53 on a kg scale
suggests that 53 is Lexicons clinical candidate LX4211 [74].
2.1.9 Janssen/MitsubishiTanabe

In 2008, an application was published claiming that in

compounds such as 55, the glucuronide of 20 were useful as
potential anti-diabetic agents by virtue of their ability to

The 2005 disclosure that N-glucosylation of 2-aminodiarylmethanes generated N-glucosides such as 56 (2.9 nM SGLT2
IC50) appeared to offer a new means to modulate SGLT2
activity especially because the potency compared favorably with
the 14nM IC50 reported for sergliflozin 3a [76,77] (Figure5).
This expectation was bolstered by the disclosures that
N-glycosylation of indoles substituted at C3 with benzyls or
methano linked heteroaryls generated potent orally active
SGLT2 inhibitors exemplified by 57 (1.1 nM IC50) and 58
(8.8 nM IC50) [78,79]. Administration of both 57 and 58 at
30 mg/kg to fed 6week-old SD rats induced sufficient glucose
excretion so that 2 2.4 g of glucose appeared in the urine
over 24 h. A subsequent application extended the scope of
N-glucosides of indoles to include modification of the
glucose moiety by replacement of either the C4 hydroxyl
with fluorine 59 or replacement of the pyranosyl oxygen with
sulfur 60 (10 nM IC50) [44]. Further elaboration taught that
incorporation of a p-cyclopropyl group in the distal ring to
generate compounds such as 61 (2.3 nM IC50) was beneficial because 2.4 g of glucose was excreted over 24h when
administered as described above to SD rats at 30 mg/kg [80].
2.2.2 Kissei

This group disclosed their findings in 2006 concerning a

nearly identical set of N-glucosides of 3-benzylated indole [81].
The limited SAR suggests that selectivity versus SGLT1 was
high unless the distal ring contained polar para functionality.
Compound 62 (0.9 nM IC50) exhibited 3500-fold selectivity
versus SGLT1; however, in vivo potency appeared to be
modest. For example, the ensuing glucose excretion response
following intravenous administration of 62 to 6 week old
male SD rats at 1 mg/kg resulted in 112mg of glucose being
excreted in urine over 24 h per 200g of body weight.
2.3 O-glucosides
2.3.1 Kissei

In 2005, an application was published which disclosed that

O-glucosides attached at C3 of indazoles phenthylated at
C4 can generate potent SGLT1 inhibitors such as 63 (12 nM
SGLT1 IC50) [82]. The limited data hinted that some
compounds within this series may even have been fivefold
selective for SGLT1 over SGLT2. Oral administration of 64
at 0.5 and 2 mg/kg to fasted STZ induced diabetic SD rats
immediately prior to administration of a high carbohydrate
liquid meal attenuated the postprandial glycemic increase at
30 min post dose by 40 and 75%, respectively; at 1 h post

Expert Opin. Ther. Patents (2009) 19(11)

1493

Evolution of sodium glucose co-transporter 2 inhibitors as anti-diabetic agents

A.

F
F
OH
N

Et

OH

OH
O

NH

S
OH

HO

OH

HO

OH
OH

OH

Et

OH

OH

OH

RO

Et

OH

57

56

58

59

Cl

HN

Cl

OH
OH

OH

OH

O
S

N
S
HO
OH

HO

OH

HO

OH

Downloaded by [Gazi University] at 07:12 12 February 2016

HO

OH

OH
OH

OH

OH

OCH3

60

61

OH

62

63

HO

F
OCH3

HO

OH

OH

OH

O
OH

OH

O
HO

HO

OH

HO
OH

OH

OH

RO
OH

Me

OH

OH

OH

OH

64

65

67

66
N

Et
O

N
HO

OH

HN
O

O
N

N
H

O
O
O

OH
Me

OH

OH

OH
HO

NH2

H
N

RO
OH

RO
OH

OH
OH

OH

HO
Me

OH

OH

69

68

B.

70

71

F
N
N

CN
N

N
N

NH2

O
O

MeO

NH2

NH2

O
Et

NH2

Cl

O
OCH3

OCH3

72

73

74

Figure5. A. O- and N-glucoside based SGLT2 inhibitors disclosed during 2005 2009. B. Atypical SGLT2 inhibitors.
SGLT2: Sodium glucose co-transporter2.

1494

Expert Opin. Ther. Patents (2009) 19(11)

75

Washburn

dose, these values diminished to 23 and 60%, respectively. It

was also disclosed that replacement of the C6 hydroxyl of
sergliflozin A 3a (9 nM IC50) with fluorine diminished
SGLT2 potency ninefold [83]. In 2006, O-glucosides of
7-hydroxyindoles either N-benzylated or N-phenethylated 65
(16 nM SGLT2 IC50; 52 nM SGLT1 IC50) were reported.
Moreover, selectivity versus SGLT1 for 65 was only
fourfold [84].

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2.3.2 DaiichiSankyo

An application disclosed a series of more polar analogues of

3a for which C5 of the central aryl ring was substituted with
either an amino or hydroxymethyl, which the limited data
suggest enhanced SGLT1 affinity. These compounds became
non-selective SGLT inhibitors, especially if the sugar moiety
had been modified by replacement of a hydrogen attached
to either C3, C4, C5 or C6 with methyl to generate
compounds such as 66 (SGLT1 and SGLT2 IC50 values of
31 and 6nM, respectively) [85].
2.3.3 BoehringerIngelheim

In 2007, an application was published disclosing the multigram synthesis, crystallization and characterization of the
crystals of the pyrazole O-glucoside 67 [86]. Presumably, 67
entered clinical trials as BI 44847. Additional pyrazole
O-glucosides were disclosed in a second application without
biological data [87].
2.3.4 Taisho

In 2004, applications were published disclosing O-glucosides

of a series of ortho benzylphenolic analogues of 3a exemplified
by 68 for which sulfur replaced the pyranosyl oxygen [88].
For this series SGLT IC50 values, determined using vesicles
prepared from rat renal membranes, ranged from 160 to
600 nM for inhibition of glucose transport. Similar activity
was also reported for analogues in which the central aryl ring
was either a pyridine or pyrazoles [89]. In 2009, this group
disclosed that polar substituents enhanced SGLT1 potency
of 68, as determined using COSK1 cells transfected with
hSGLT1/2. Specifically, hydroxylation of C5 of the central aryl
ring and attachment of polar amides or ureas either directly
or via an alkyl tether at C4 of the distal ring generated SGLT1
selective inhibitors exemplified by 69 (SGLT1 and SGLT2
IC50 values of 13 and 341 nM, respectively) [90]. A concurrent application disclosed that potent SGLT1 inhibitors
exhibiting 1000-fold selectivity versus SGLT2 could be obtained
upon replacement of the central phenolic ring of 68 with a
pyrazole provided that the distal ring was substituted with
polar amides [91]. For example, 70 exhibited IC50 values of
22 and 7600 nM versus SGLT1 and SGLT2, respectively,
in the transfected COSK1 cell assay. When administered
at 1 mg/kg to streptozotocin induced diabetic SD rats
immediately prior to a liquid meal, analogues of both 69
and 70 reduced the glucose excursion in an OGTT at 1h by
greater than 50%.

2.3.5 Chugai

In 2006, this group disclosed that the glucoside moiety of

O-glucosides of ortho-benzylphenols such as 3a could be replaced
with perhydroxylated cyclohexyl ethers to generate novel active
SGLT2 inhibitors such as 71 (7 nM SGLT2 IC50) [64].
2.4 Non-glucoside

containing SGLT2inhibitors

2.4.1 MerckGMBH

Merck published three patents in 2008 and a fourth in 2009

which disclosed radically different SGLT2 inhibitors. In all
instances, the pharmacophore and the spatial presentation of the
appendages remained the same; however, for each series a different bicyclic heterocycle core indolizine, benzoimidazole,
imidazo[1,2]pyridine and imidazo[1,2]pyrimiidine was used
for which respective representative examples are 72 75 [92-95].
Specific SGLT1 and SGLT2 IC50 values, determined using
hSGLT transfected BHK cells, were not disclosed; instead
ranges were reported. For the most selective members of each
series, the SGLT1 IC50 was reported as > 10,000 nM; whereas
SGLT2 IC50 was reported as 10 1000 nM except for the
indolizine series 72 for which SGLT2 IC50 was reported as
1000 10,000 nM. No invivo data were provided nor any
discussion regarding the mechanism by which glucose transport
wasdisrupted.
3. Conclusion

Three findings have influenced the evolution of competitive

SGLT2 inhibitors: i) the demonstrated potential of SGLT2
inhibitors as anti-diabetic agents in diabetic animal models
following modification of phlorizin to generate O-glucosides
of dihydrochalcones such as T-1095 by Tanabe; ii) the disclosure by Bristol-Myers Squibb that a different spatial presentation was required for C-glucoside SGLT2 inhibitors than for
O-glucosides; and iii) the realization that O-glucosides were
not competitive to date with C-glucosides due to a huge
differential in in vivopotency.
Structurally diverse, presumably competitive SGLT2 inhibitors, exhibiting IC50 values < 10nM, can be readily obtained
regardless whether an O, C or N-glucoside is used. For all,
the underlying pharmacophore is the same: a diarylmethane
moiety or heterocycle equivalent attached to a glucose moiety.
Both O- and N-glucosides require ortho substitution of the
central aryl ring to achieve optimal spatial presentation of the
glucoside and distal ring whereas C-glucosides require meta
substitution. N-glucosides appear to be approximately fivefold more potent SGLT2 inhibitors than the corresponding
O-glucoside. For C-glucosides, the limited invitro data suggest
replacement of the pyranosyl oxygen with a sulfur or methylene
reduced SGLT2 potency three and sixfold, respectively; conversion of the C6 glucosyl hydroxyl to a fluoride reduced SGLT2
potency approximately ninefold. For all three glucoside families,
the aglycone substituents appear to exhibit similar SAR for
potency and selectivity such that substitution of the distal ring
with a large polar para substituent increases SGLT1affinity.

Expert Opin. Ther. Patents (2009) 19(11)

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Evolution of sodium glucose co-transporter 2 inhibitors as anti-diabetic agents

Table1. SGLT2 potency and selectivity disclosed for

SGLT2 inhibitors that entered clinical trials.
Clinical
candidate

Structure

SGLT2
IC50 (nM)

Selectivity
versus SGLT1

Dapagliflozin
BMS-512148

1.1

1200

BI 10773*

24, 33 or 34

3.1

> 2500 [96]

Canagliflozin
TA-7284

20

2.2

200 [97]

ASP 1941*

11

8.4

LX4211*

53

C-glucosides

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O-glucosides
T-1095A

2a

6.6

30 [33]

Sergliflozin A

3a

> 800 [33]

Remogliflozin

4a

14

1100 [33]

*Undisclosed structure inferred from a patent describing large scale preparation

and pharmaceutical characterization of crystalline finalform.
SGLT: Sodium glucose co-transporter.

The Merck inhibitors 72 75 represent a totally different

approach. From the data presented, one cannot ascertain
whether these compounds inhibit SGLT2 directly, although
presumably not as competitive inhibitors given the structural
dissimilarity from glucose, or indirectly by acting downstream
of SGLT2 to prevent cellular uptake of glucose. For example,
one possibility could be inhibition of the Na+/K+ ATPase pump
required to maintain low intracellular Na+ concentration that
drives the co-transport of glucose and Na+.
4. Expertopinion

With respect to in vivo potency, the superiority of

C-glucosides over O-glucosides possibly reflects a combination
of reduced bioavailability and faster clearance presumably due
in part to glucosidase mediated hydrolysis of the O-glucoside
bond [33]. At present, there are no currently active clinical
trials with O-glucosides; clinical studies with the O-glucoside
SGLT2 inhibitors, T-1095, sergliflozin, remogliflozin, TS-033,
AVE 2268 and BI 44847, have all been discontinued. Given
these disappointments, prospects are justifiably poor that any
additional O-glucosides will enter the clinic. Assessment of
the therapeutic potential of N-glucosides is difficult because
no PK data or clinical results with an N-glucoside have been
reported. Given the encouraging disclosures of Tanabe and
Kissei regarding the glucose excretion response induced by 57
and 62, the absence of more advanced studies suggests that
the N-glycoside linkage may confer an as yet undisclosed
liability that precluded furtherprogression.
Theoretically, the glucose excretion response and the
concomitant reduction in glycemic level would be significantly
1496

greater if non-selective SGLT2 inhibitors were used for

type 2 diabetics because non-selective SGLT1/2 inhibitors
could modulate 100% of the renal glucose recovery rather
than the 67% that appears to be modulated by selective
SGLT2 inhibitors. However, commercial prospects for nonselective SGLT2 inhibitors or SGLT1 inhibitors do not appear
encouraging due to the possibility that glucosegalactose
malsorption side effects may become dose limiting. Because
the projected pharmacological profile should emulate that of
the -glucosidase inhibitor acarbose, efficacy achieved with
either as an anti-obesity agent or anti-diabetic may be constrained by patient tolerability of the same gastrointestinal
side effects that have precluded wide-spread acceptance of
acarbose. In addition, the potential cardiac risk arising from
inhibition of SGLT1 in the heart has yet to be determined.
Presumably for these reasons, all the SGLT2 inhibitors that
entered clinical trials exhibited greater than 100-fold selectivity
versus SGLT1 except for T-1095A.
Many of the concerns voiced regarding utilization of SGLT2
inhibitors as anti-diabetics have yet to be manifested in clinical
findings. In particular, the incidence of urinary tract infections
was not elevated over that observed for the placebo control or
metformin treated cohort. Polyuria has not been an issue; over
a 24 h period, the increase in urine volume corresponded to
one additional voiding nor were changes in electrolyte composition (Na+, K+ Cl-) significant. In fact, diuretics used for
hypertension such as furosemide induce far greater perturbations in both volume and electrolytes. No changes in GFFR were
noted suggesting that renal function was not impacted. Hypoglycemia has not been an issue. PhaseIII results will provide
a better perspective regarding the observed dose-dependent
increase in the incidence of genital tractinfection.
Over the past 10years, the utilization of SGLT2 inhibitors
for treatment of diabetes has evolved from a concept to an
approach exhibiting promise in the clinic although no SGLT2
inhibitor has yet completed PhaseIII. At present, clinical trials
are in progress with five C-glucosides: dapagliflozin (BrystalMyers Squibb), BI 10773 (Boehringer Ingelheim), TA-7284
(Johnson and Johnson), ASP 1941 (Astellas) and LX4211
(Lexicon) (Table 1). All share a commonpharmacophore.
The clinical studies with type2 diabetic subjects reported
to date revealed that selective SGLT2 inhibitors can reduce
placebo subtracted HbA1C levels as much as 0.7% accompanied with modest weight reduction. These benefits were
obtained with type 2 diabetics at all stages of the disease
early, mid and late even with those on insulin therapy
exhibiting inadequate glycemic control. In addition, the
modest diuretic effect induced sufficient volume depletion
to effect a modest reduction in systolic blood pressure. For
those patients either in the early or mid-stage of the disease,
SGLT2 inhibitors should enhance -cell preservation because
curtailment of postprandial glucose excursions would ameliorate insulin demands. The fact that this class of anti-diabetics
is not dependent on insulin provides flexibility for use as well
as a margin of safety with respect to hypoglycemia. There is

Expert Opin. Ther. Patents (2009) 19(11)

Washburn

reason to expect these SGLT2 inhibitors will become an

important addition for the treatment of diabetes whether
administered as first-line therapy or as an add-on to existing
medications such as metformin or eveninsulin.

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Affiliation
William N Washburn
Senior Research Fellow,
Metabolic Diseases Chemistry,
Research and Development,
Bristol-Myers Squibb Co.,
P.O. Box5400, Princeton, NJ 08543, USA
Tel: +1 609 818 4971; Fax: +1 609 818 3550;
E-mail: william.washburn@bms.com

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