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

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Expert Opinion on Therapeutic Patents

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

William N Washburn

To cite this article: William N Washburn (2009) Evolution of sodium glucose co-transporter 2inhibitors as anti-diabetic agents, Expert Opinion on Therapeutic Patents, 19:11, 1485-1499

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10.1517/13543770903337828 © 2009 Informa UK Ltd ISSN 1354-3776 1485All rights reserved: reproduction in whole or in part not permitted

Evolutionofsodiumglucoseco-transporter2inhibitorsasanti-diabeticagentsWilliam N WashburnMetabolic Diseases Chemistry, Research and Development, Bristol-Myers Squibb Co., P.O. Box 5400, Princeton, NJ 08543, USA

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 in vivo potency of O-glucosides was markedly less than that of C-glucosides neces-sitated 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 clinical trials.

Keywords: canagliflozin, C-glucoside, C-glycoside, dapagliflozin, phlorizin, remogliflozin, sergliflozin, SGLT, SGLT2, type 2 diabetes

Expert Opin. Ther. Patents (2009) 19(11):1485-1499

1. Introduction

1.1 RoleofthekidneyThe 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 glom-erular 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 Figure 1, 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)

1. Introduction

2. Patent review

3. Conclusion

4. Expert opinion

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Evolutionofsodiumglucoseco-transporter2inhibitorsasanti-diabeticagents

1486 ExpertOpin.Ther.Patents(2009) 19(11)

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 contribu-tor 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 concen-tration 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 facilita-tive GLUT1 and GLUT2 transporters. The SGLT2 trans-porter 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 glucose–galactose 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

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phenotype presented by humans bearing SGLT2 mutations, most pharmaceutical efforts have focused on devising inhibitors selective for the SGLT2 transporter.

1.2 AmeliorativeroleofSGLT2inhibitorsfortype2diabetesThe hallmarks of type 2 diabetes are β-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, β-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 non-insulin 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 resis-tance and demands on pancreatic β cells resulting in a pro-gressive 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 ModulationofSGLT2Renal 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 (Figure 2); 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

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ExpertOpin.Ther.Patents(2009) 19(11) 1487

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 allosteric modulation.

The natural product phlorizin 1 has been a well-known glucosuric agent for > 100 years 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 entail-ing 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]. Subse-quent 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 of tissues.

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 pre-dominant 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 in vivo 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.

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Figure2.SGLT2inhibitorspredating2005.SGLT2: Sodium glucose co-transporter 2.

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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 distri-bution 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 com-plexes 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,acasestudyDapagliflozin 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 3 nM 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 24 h. When administered to diabetic ZDF rats with fasting blood glucose levels of 350 mg/dl, dose-dependent glucose excretion correlated with progressive reduc-tions in glycemic levels such that near normalization was achieved with 1 mg/kg at 6 h post dose. Following subchronic administration for 2 weeks, 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 3 days following completion of the study.

Clinical studies with dapagliflozin have been very encouraging [32-34]. The PK profile is amenable to daily administration; tmax is ∼ 1 h; t1/2 in humans is ∼ 15 h. When administered to healthy volunteers, the 20 mg dose produced a maximum pharmacodynamic response resulting in 55 – 60 g 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 360 g, excretion of 60 g 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

glucose levels for the duration of the study. For these individuals, the mean amount of glucose excreted over 24 h 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 100 mg dose. When dapagliflozin was administered to type 2 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 subtrac-tion [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, Phase III studies are in progress with dapagliflozin.

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 in vitro evaluation; the reader can assume these cell lines were used unless otherwise stated.

2.1 C-glucosidesThe 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 pre-sentation 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 SGLT2 inhibitors.

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

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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 planar ring.

2.1.1 Kotobuki/AstellasIn 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 deter-mining 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 8 h 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.

2.1.2 KisseiTwo 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 benzothio-phenes 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; how-ever, the ethano linked 15 exhibited only fourfold selectivity for SGLT2. In the second application, C5 glycosylated benzothiophenes were benzylated at C3 to generate com-pounds 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

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 adminis-tration of this chemotype to 6 week 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/MitsubishiIn 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 sub-stituted 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 6 week-old male SD rats. A subsequent application in 2008 described preparation and properties of a crystalline semi-hydrate of 20 amenable for incorporation in pharma-ceuticals [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 > 2400 mg of glucose.

2.1.4 Boehringer IngelheimThe Boehringer Ingelheim group, capitalizing on the narrow definition for substituents in the initial Bristol-Myers Squibb C-glucoside application, focused primarily on the identifica-tion 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 encom-passed 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 heteroaro-matics 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].

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Figure3.C-glucosidebasedSGLT2inhibitorsdisclosedduring2005–2009byKotobuki/Astellas,Kissei,Tanabe/MitsubishiandBoehringerIngelheim.SGLT2: Sodium glucose co-transporter 2.

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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 dialky-lphosphinoyl 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. Replace-ment 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 pub-lished 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 1000 nM, particularly less than 200 nM, 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 TaishoIn 2006, an application was published extending Taisho’s 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 corre-sponding 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 chemo-type which were substituted at C4 and C4′ exhibited SGLT2 IC50 values of ∼ 100 nM 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 20 nM for SGLT1 and SGLT2, respectively). Oral administration of 37 at 1 mg/kg to db/db mice reduced the 24 h 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 17 nM, respectively) could be obtained upon replacement of the distal aryl C4 methyl of 37 with hindered hydroxylated amides of ω-substituted propanoic, butanoic and pentanoic carboxylic acids [61]. Oral adminis-tration of 38 at 1 mg/kg 5 min prior to a glucose solution (2 g/kg) produced a 70% reduction in the 1 h 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 17 nM were iden-tical 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 ChugaiThis 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 diaryl-methane 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 in vitro structure–activity 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 counter-part 8 but selectivity versus SGLT1 was diminished fourfold. Oral administration of 46 at 0.3 mg/kg to 11 week-old db/db mice reduced blood glucose levels by 52 and 25% at 6 and 24 h 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

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SOH

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39 40

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54 55

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52

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OH

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Figure4.C-glucosidebasedSGLT2inhibitorsdisclosedduring2005–2009byTaisho,ChugaiSelyakuKabushiki,Theracos,LexiconandJansen/Mitsubishi/Tanabe.SGLT2: Sodium glucose co-transporter 2.

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counterpart 45 [67]. Also in 2008, an application was pub-lished 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.

2.1.7 TheracosIn 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 < 1000 nM. 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 alkyla-tion to generate a series of ethers exemplified by the three butynyl ethers 50 [70]. Also in 2008, an application was pub-lished 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 function-ality 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 with proline.

2.1.8 LexiconIn 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 in vitro evaluation of SGLT1/2 IC50 values using hSGLT1/2 transfected HEK293 cells and in vivo 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 Lexicon’s clinical candidate LX4211 [74].

2.1.9 Janssen/Mitsubishi TanabeIn 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

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.

2.2 N-glucosides2.2.1 Tanabe SeiyakuThe 2005 disclosure that N-glucosylation of 2-aminodiaryl-methanes 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 14 nM IC50 reported for sergliflozin 3a [76,77] (Figure 5). 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 6 week-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 benefi-cial because ≥ 2.4 g of glucose was excreted over 24 h when administered as described above to SD rats at 30 mg/kg [80].

2.2.2 KisseiThis 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 112 mg of glucose being excreted in urine over 24 h per 200 g of body weight.

2.3 O-glucosides2.3.1 KisseiIn 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

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72 7473 75

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Figure5.A. O- and N-glucoside based SGLT2 inhibitors disclosed during 2005 – 2009. B. Atypical SGLT2 inhibitors.SGLT2: Sodium glucose co-transporter 2.

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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].

2.3.2 Daiichi SankyoAn 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 6 nM, respectively) [85].

2.3.3 Boehringer IngelheimIn 2007, an application was published disclosing the multi-gram 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 TaishoIn 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 concur-rent 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 1 h by greater than 50%.

2.3.5 ChugaiIn 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-glucosidecontainingSGLT2inhibitors2.4.1 Merck GMBHMerck 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 dif-ferent 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 in vivo data were provided nor any discussion regarding the mechanism by which glucose transport was disrupted.

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 disclo-sure by Bristol-Myers Squibb that a different spatial presen-tation 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 vivo potency.

Structurally diverse, presumably competitive SGLT2 inhibi-tors, exhibiting IC50 values < 10 nM, 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 five-fold more potent SGLT2 inhibitors than the corresponding O-glucoside. For C-glucosides, the limited in vitro data suggest replacement of the pyranosyl oxygen with a sulfur or methylene reduced SGLT2 potency three and sixfold, respectively; conver-sion 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 SGLT1 affinity.

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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 further progression.

Theoretically, the glucose excretion response and the concomitant reduction in glycemic level would be significantly

Table1.SGLT2potencyandselectivitydisclosedforSGLT2inhibitorsthatenteredclinicaltrials.

Clinicalcandidate

Structure SGLT2IC50(nM)

SelectivityversusSGLT1

C-glucosides

DapagliflozinBMS-512148

8 1.1 1200

BI 10773* 24, 33 or 34 3.1 > 2500 [96]

CanagliflozinTA-7284

20 2.2 200 [97]

ASP 1941* 11 8.4

LX4211* 53

O-glucosides

T-1095A 2a 6.6 30 [33]

Sergliflozin A 3a 9 > 800 [33]

Remogliflozin 4a 14 1100 [33]

*Undisclosed structure inferred from a patent describing large scale preparation

and pharmaceutical characterization of crystalline final form.

SGLT: Sodium glucose co-transporter.

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 non-selective SGLT2 inhibitors or SGLT1 inhibitors do not appear encouraging due to the possibility that glucose–galactose malsorption side effects may become dose limiting. Because the projected pharmacological profile should emulate that of the α-glucosidase inhibitor acarbose, efficacy achieved with either as an anti-obesity agent or anti-diabetic may be con-strained 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 com-position (Na+, K+ Cl-) significant. In fact, diuretics used for hypertension such as furosemide induce far greater perturba-tions in both volume and electrolytes. No changes in GFFR were noted suggesting that renal function was not impacted. Hypo-glycemia has not been an issue. Phase III results will provide a better perspective regarding the observed dose-dependent increase in the incidence of genital tract infection.

Over the past 10 years, 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 Phase III. At present, clinical trials are in progress with five C-glucosides: dapagliflozin (Brystal-Myers Squibb), BI 10773 (Boehringer Ingelheim), TA-7284 (Johnson and Johnson), ASP 1941 (Astellas) and LX4211 (Lexicon) (Table 1). All share a common pharmacophore.

The clinical studies with type 2 diabetic subjects reported to date revealed that selective SGLT2 inhibitors can reduce placebo subtracted HbA1C levels as much as 0.7% accom-panied 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 β-cell preservation because curtailment of postprandial glucose excursions would amelio-rate 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

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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 even insulin.

Declarationofinterest

The author is an employee of Bristol-Myers Squibb and may own stock in the company.

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AffiliationWilliam N WashburnSenior Research Fellow, Metabolic Diseases Chemistry, Research and Development, Bristol-Myers Squibb Co., P.O. Box 5400, Princeton, NJ 08543, USA Tel: +1 609 818 4971; Fax: +1 609 818 3550; E-mail: [email protected]

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Documents

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