Copyright 2009 by the American Chemical Society
Volume 52, Number 7
April 09, 2009
PerspectiVe Development of the Renal Glucose Reabsorption Inhibitors: A New Mechanism for the Pharmacotherapy of Diabetes Mellitus Type 2 William N. Washburn† Metabolic Diseases Chemistry, Research and DeVelopment, Bristol-Myers Squibb Co., P.O. Box 5400, Princeton, New Jersey 08543 ReceiVed October 15, 2008
Introduction a
Diabetes mellitus type 2 (T2DM ), comprising 90% of all cases of diabetes mellitus,1 is a growing public health problem in developed and developing nations alike. In 2007, the number of people worldwide with diabetes mellitus was estimated to be 246 million, and this number is estimated to reach 380 million by 2025.2 In 2005 in the U.S. alone, an estimated 20.6 million individuals (9.6% of the adult population) had diabetes.1 The economic burden of diabetes in the U.S. in 2002 was estimated to be $92 billion in direct medical costs and $40 billion in disability, work loss, and premature death.1 The burden of diabetes is driven by vascular complications such as cardiovascular disease, stroke, nephropathy, retinopathy, renal failure, and amputations of the extremities.1 Although these complications result from multiple metabolic derangements, hyperglycemia is central to both the vascular consequences of diabetes and the progressive nature of the disease itself. Chronically elevated blood glucose levels have been shown to result in higher protein glycation, reduced insulin secretion, β cell apoptosis, increased oxidative stress, and heightened insulin resistance.3 Moreover, these effects can be reduced with tight glycemic control. Results from the United Kingdom Prevention of Diabetes Study (UKPDS) showed that incremental reductions in glycosylated hemoglobin (HbA1C), a marker of protein glycation, lowered the risk of diabetes-related events, including † Phone: 609-818-4971. Fax: 609-818-3550. E-mail: william.washburn@ bms.com. a Abbreviations: T2DM, diabetes mellitus type 2; HbA1C, glycosylated hemoglobin; GLUT, sodium-independent facilitative glucose transporter; SGLT1, sodium-glucose co-transporter 1; SGLT2, sodium-glucose cotransporter 2; SAR, structure-activity relationship; PPG, postprandial glucose; OGTT, oral glucose tolerance test; AUC, area under the curve; SAD, single ascending dose; MAD, multiple ascending dose; FSG, fasting serum glucose; AE, adverse event.
Table 1. Target Organs and HbA1C Reductions with Current Oral Antidiabetic Medications therapeutic class
agent
biguanides thiazolidinediones
targeted organ
metformin liver, intestines, pancreas rosiglitazone liver, adipose tissue, skeletal muscle DPP-4 inhibitors sitagliptine intestine sulfonylureas glimepiride pancreas R-glucosidase inhibitors acarbose pancreas, small intestines incretin mimetics exenatide pancreas glinides repaglinide pancreas pramlintide
HbA1C reduction (%) 1.0-2.0 0.5-1.0 0.6-1.4 1.0-2.0 0.5-1.0 0.5-0.9 1.0-1.5
myocardial infarction and microvascular complications.4 Thus, reducing HbA1C values to 1000-fold selectivity for SGLT2 than SGLT1.34 These advantages, in addition to that conferred by the hydrolytic resistance of C-arylglucosides to glucosidases, shifted our focus from O-glucosides. Further SAR exploration of the central aryl ring revealed that small lipophilic substituents at the C4′ position of the central aryl ring further increased SGLT2 affinity such that EC50 values decreased to 1
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Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7 1789
Figure 6. Discovery of SGLT2 spatial preference for meta-substituted C-aryl glucosides.
Figure 7. Structure-activity relationship for diarylmethane C-glucoside SGLT2 inhibitors.
nM. Although substitution at C5′ or C6′ modestly improved affinity, C2′ substitution was deleterious.34 This effort culminated in the discovery of 16 (dapagliflozin, BMS-512148), which subsequently has exhibited sufficient promise to warrant initiation of phase III clinical studies in 2007. In vitro characterization of 16 revealed the EC50 to be 1.1 and 3.0 nM for the hSGLT2 and rSGLT2 transporters, respectively.36 Selectivity vs the corresponding SGLT1 transporters was 1200and 200-fold, respectively. No significant inhibition was observed for GLUT1 and GLUT4 at 20 µM. No off-target
interactions were detected upon evaluation of 16 in a diverse set of enzymatic, transporter, receptor, and ion channel assays.34 Following our disclosure that meta substitution of the central aryl ring is required for the pendent glucoside moiety and the tethered distal aryl ring, a number of diverse novel structures have been devised to achieve this spatial presentation.30 Compounds 17-22 exemplify these efforts (Figure 8).37-41 It is noted that SGLT2 inhibition is not limited to low molecular weight glucosides. Two other approaches targeting inhibition of renal glucose reabsorption are in preclinical development. One uses antisense molecules exemplified by ISIS 388626 to reduce expression of SGLT2; the other uses SGLTspecific peptide antagonists.42,43 Because of the paucity of disclosed biological data, and in particular the absence of early clinical disclosures pertaining to C-glucoside- as well as to most O-glucoside-based SGLT2 inhibitors, the ensuing analysis of the potential of SGLT2 inhibitors as antidiabetic agents will be exemplified primarily with clinical results obtained with 16 and 6b. Preclinical in ViWo Studies The abilities of O-glucoside-based SGLT2 inhibitors to blunt postprandial glucose (PPG) excursions, promote glucosuria, and reduce hyperglycemic levels in normal and diabetic rats are well established.18-22,26 The in vivo profile of 16 suggests that C-glucoside based inhibitors are no different. When administered at 0.1-1.0 mg/kg to normal and diabetic rats, 16 dose-
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PerspectiVe
Figure 8. Representative examples of C-aryl glucoside SGLT2 inhibitors.
Figure 9. Weight loss after multiple doses of dapagliflozin in diet-induced obesity rats. Dapagliflozin produced significant (P < 0.05) weight loss for each dose. If the compound-induced overeating was prevented, then the weight loss was greater than when overeating was not prevented.44
dependently increased glucosuria, resulting in urinary glucose excretion of up to 1.0 g/day without causing hypoglycemia. An oral glucose tolerance test (OGTT) test revealed that doses of 1 and 10 mg/kg reduced the glucose AUC of normal rats by 30% and 50%, respectively, thereby demonstrating the ability to blunt PPG excursion.36 In a 15-day study with 17-week-old male ZDF rats, once-daily treatment with 0.1-1.0 (mg/kg)/day of 16 continually improved plasma glucose levels in a dose dependent fashion such that fasting glucose levels decreased from 300 to 100 mg/dL and postprandial glycemic levels diminished from 480 to 270 mg/dL over the 2-week course. Upon completion of the study, analysis employing a hyperinsulinemic euglycemic clamp revealed that treatment with 16 improved key aspects of metabolic dysregulation in ZDF rats.
In this model, a significant increase in glucose infusion rate (GIR) was accompanied by a significant reduction in endogenous glucose production measured on the third day following the final dose (P < 0.01 vs vehicle controls for both outcomes).36 In a 4-week study with diet-induced obese Sprague-Dawley male rats weighing ∼750 g, 16 produced weight losses of 3.9%, 4.2%, and 5.5% relative to vehicle when administered at 0.5, 1, and 5 (mg/kg)/day, respectively (Figure 9).44 Pair feeding of the 5 mg/kg cohort to vehicle to prevent compensatory food consumption increased the weight loss to 12.3%. No behavioral evidence suggestive of hypoglycemia was noted. Evidence for greater utilization of fat as an energy source was (1) a decrease in respiratory quotients from 0.87 for controls to 0.77 for drugtreated rats on day 2 and 0.80 on day 15 and (2) dose-dependent
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increases in 3-hydroxybutyrate levels on day 28 from 6 mg/dL for vehicle treated to 26, 32, and 50 mg/dL for the rats administered 0.5, 1, and 5 mg doses, respectively. Treated animals lost adipose mass, not lean body mass.44 In summary, these finding suggest that 16 exhibits potential for inducing clinically meaningful weight loss in addition to treating diabetes.
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7 1791 Table 3. Dose-Dependent Urinary Glucose Excretion Over 24 h after Oral Administration of Selected SGLT2 Inhibitors to Normal Sprague-Dawley Rats drug-induced urinary glucose (mg) excreted over 24 h by SD rats per 200 g body weight dose (mg/kg)
1635
0.1 1.0 3 10 30 100 300
550 1100
Comparison of C-Glucosides with O-Glucosides The dose responses for urinary glucose excretion induced in normal Sprague-Dawley rats over 24 hr following oral administration of 16, 5b, 6b, 3b, or 1 suggest that the efficacy may be comparable for O- and C-glucosides, as the maximum response of both 3b and 16 appear to be somewhat greater than 2000 mg of glucose. (Table 3) Comparison of the dose of each agent required to promote loss of ∼500 mg of glucose reveals 16 to be at least 100-, 300-, 300-, and 3000-fold more potent than 5b, 6b, 3b, and 1 respectively. Since the corresponding differentials for in vitro SGLT2 affinities are 13, 8, 6, and 30 (Table 2), inherent affinity cannot account for the superior in vivo potency of 16. Given the susceptibility of these Oglucosides to glucosidase-mediated degradation, we attribute the greater in vivo potency of 16 in part to the inherent stability of the C-glucoside bond which ensured a longer duration of action. Clinical Trials of 16 A single ascending dose (SAD) study revealed 16 to be well tolerated by healthy adult volunteers receiving doses ranging from 2.5 to 500 mg/day (16 placebo, 6 per drug arm).45 16 was rapidly absorbed; median Tmax was 1 h. For the 10-100 mg doses, mean t1/2 and clearance were ∼15 h and ∼6 mL/min, respectively. In a 2-week multiple ascending dose (MAD) clinical study with healthy volunteers (10 placebo, 6 per drug arm), the cumulative 24 h glucose excreted in urine did not significantly change from day 1 to day 14.45 No apparent effect on urinary calcium, magnesium, sodium, potassium, phosphate, chloride, oxalate, citrate, total protein, albumin, osmolality, or β2-microglobulin was observed. Comparable levels of urinary glucose output (∼55-60 g over 24 h) were obtained following the 20, 50, and 100 mg doses, whereas the response from the 2.5 and 10 mg doses was 33% and 70%, respectively, of this value. In both studies 16 was well tolerated with no serious AEs noted. All reported adverse events were mild to moderate and not dose-dependent. The AE incidence was 21% and 37%, respectively, for drug recipients in the SAD and MAD studies and 35% for the placebo arms. 16 has been evaluated in a 2-week study of 47 patients with T2DM who were drug naive or previously treated with metformin at baseline.46 In this randomized, double-blind, placebocontrolled phase IIA trial, patients with fasting serum glucose (FSG) of e240 mg/dL received either placebo (n ) 8) or 5 mg (n ) 11), 25 mg (n ) 12), 100 mg (n ) 16) of 16 once daily. A constant rate of glucosuria was observed over 24 h (2 g/h induced by the 5 mg/d dose and 3 g/h following the 25 and 100 mg/d doses (Table 4).46 In the SAD, MAD, and phase 2A studies, the mean amount of glucose excreted over 24 h plateaued at 70-80 g, a value that corresponded to ∼40% of the ∼180 g/day filtered by the kidney.47 These findings suggest that glucose recovery can also be potentially mediated by some means other than SGLT2. Consequently, utilization of selective SGLT2 inhibitors that do not impact this alternative route would further minimize the potential for hypoglycemic events to be incurred by this therapeutic approach, since partial recovery of glucose from the glomerular filtrate would be maintained.
1900
5b26 36 95 320
6b18
80 180 400
3b19
119
50 450 1000 2000
80
Table 4. Changes in Glucose Excretion in Urine, FSG, and PPG of Diabetics after Administration of 16 in a 14 Day MAD Study46 dose of 16 parameter cumulative glucose excreted in urine over 24 h on day 1 cumulative glucose excreted in urine over 24 h on day 14 % decrease in FSG on day 2 from baseline % decrease in FSG on day 13 from baseline % decrease in PPG on day 2 from baseline % decrease in PPG on day 13 from baseline a
placebo 5 mg/day 25 mg/day 100 mg/day 2g
45.3 ga
75.3 ga
81.3 ga
2g
36.6 ga
70.1 ga
69.9 ga
-1.2% -7.0%
7.5%
9.3%a
5.2%
11.7%a
13.3%a
21.8%a
2.5%
9.6%a
13.2%a
11.7%a
5.2%
17.6%a
22.6%a
18.8%a
P < 0.05.
Reductions in both FSG and PPG observed in patients treated with 16 were dose-dependent and progressive, increasing over the 2-week period. Changes in FSG from baseline (day -2) became significant at day 2 of treatment only for those patients receiving 100 mg/d of 16; however, FSG levels were significantly reduced for all three doses of 16 on day 13 of treatment (Table 4).46 Significant improvement in PPG was observed in all three treatment groups on both days 2 and 13 of treatment vs baseline (Table 4). No significant change in either FSG or PPG was observed for the placebo-treated group. These results establish that once-daily dosing of 16 can achieve reductions in FSG and PPG. 16 appeared to be well tolerated, as there were no discontinuations due to AEs in this short-term study. The incidence of the most commonly reported AEs (constipation, nausea, and diarrhea), which was similar for groups treated with 16 or placebo, was associated with concurrent use of metformin. Two cases of hypoglycemia, which occurred in patients receiving both dapagliflozin and metformin, and two cases of vulvovaginal infection were the most notable AEs observed. Recently reported results from a 12 week phase IIB study comprising 389 T2DM patients provide further confirmation of both the efficacy and safety of 16 in T2DM patients.48,49 At week 12 following daily administration of 2.5, 5, 10, 20, and 50 mg of 16, mean reductions in HbA1C were 0.71%, 0.72%, 0.85%, 0.55%, and 0.90%; the corresponding % decrease for the placebo and metformin XR (750 mg titrated to 1500 mg) arms was 0.18% and 0.73%. In addition, body weight of the patients was reduced in a dose-related fashion, resulting in a loss of 2.3-3.4% versus 1.2% for placebo.50 The most common adverse events were urinary tract infection, nausea, dizziness, headache, fatigue, back pain, and nasopharyngitis. The incidence of reported but unverified hypoglycemic events was higher than placebo but similar to that of metformin, a hyperglycemic agent known to present little risk of hypoglycemia. No clinically
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meaningful changes in serum sodium, potassium, or calcium levels were detected, but serum magnesium was elevated and phosphate was reduced. Currently phase III studies with 16 are in progress. Clinical Studies with Other SGLT2 Inhibitors Several other SGLT2 inhibitors are also being actively evaluated in the clinic. GSK/Kissei had completed several phase II studies with 6b as an antidiabetic agent before apparently replacing it with 5b.51,52 In addition, 6b was also evaluated as an antiobesity agent in a 3-month study entailing t.i.d. administration. A 3-month phase IIB antidiabetic study is in progress with 5b.52 Sanofi-Aventis completed a phase IIB study with AVE 2268 (23) in 300 patients for which the doses were 300, 600, and 1200 mg qd and 1200 mg b.i.d.; however, subsequent progression of 23 has been discontinued.52,53 Similarly, Taisho, after conducting a phase II study in Japan with TS-033 (24), halted clinical progression of 24 in favor of an alternative undisclosed candidate. 52,54 Astellas has completed a 3-month phase IIB study with the C-glucoside 17 (YM-543).52,55 Boehinger-Ingelheim has evaluated two SGLT2 inhibitors, BI 10773 (25) and BI 44847 (26), in a 4-week phase I/IIA study in diabetics.52,56 The dosing regimen of 26 entailing b.i.d. doses of 100, 400, and 800 mg suggests that 26 is an O-glucoside which was licensed from Ajinomoto. In contrast, the q.d. dosing regimen of 25 consisting of 10, 25, and 100 mg is suggestive of a C-glucoside structure. Phase IIB studies have been initiated with 25 which can be inferred from the extensive recent Boehinger-Ingelheim C-arylglucoside patent disclosures to be a close structural analogue of 16. The joint development by J&J/Tanabe Seiyaku of the O-glucoside 3b as an antidiabetic appears to have ceased.57 Mitsubishi Tanabe Pharma and J&J are codeveloping a replacement compound, TA-7284, which has progressed to phase II trials.52 Despite the extensive number of studies listed in the clinical trials database, only GSK and Sanofi-Aventis have disclosed any clinical results. Sanofi-Aventis disclosed the urinary glucose excreted over 24 h following administration of a single 1.2 and 2 g dose of 23 to healthy volunteers.58 GSK reported that in two early phase 1 single dose studies, 6b was well tolerated when administered at doses of 5-500 mg to healthy males and diabetics. Dose dependent urinary glucose excretion was observed to plateau at the higher doses in both studies.58 The duration of glucose excretion paralleled plasma levels of 6a. A 2 week study entailing t.i.d. administration of 6b at 500 or 1000 mg/day to overweight subjects produced a dose dependent increase in urinary glucose excretion accompanied by 1.5 kg reduction in body weight without any symptoms of hypoglycemia.58a The most common AEs were headache, nausa, dizziness, and flatulence. When administered at 500 mg to healthy T2DM, 6b decreased plasma glucose concentrations by 7 mmol · h/L over a 4 h period following an OGTT test.58b Comparison of findings from and doses utilized in SAD studies with 23 and 6b with that of 16 reveals 16 to be a much more potent glucosuric agent over 24 h (Table 5).59,60 Just as was observed in rodents, all indications are that O-glucoside containing SGLT2 inhibitors will require much higher doses and sometimes b.i.d./t.i.d. administration to compensate for either the presumed more rapid clearance mediated in part by glucosidases or lower bioavailability in order to achieve clinical efficacy comparable to that of C-glucosides such as 16. Because of this metabolic instability, progression of O-glucosides appears to be inherently more difficult than that of C-glucosides because of (1) the higher drug burden to compensate for enzymatic
PerspectiVe Table 5. Comparison of Urinary Glucose Excretion Over 24 h in Healthy Normal Volunteers after Oral Administration of Selected SGLT2 Inhibitors drug
dose (mg)
glucose output over 24 h (g)
6b51
200 500 1200 2000 5 20
12 17 14 21 ∼32 ∼64
2353 1645
degradation and (2) the need to establish that significant GLUT inhibition does not result from aglycone release. Conclusions Selective inhibition of the SGLT2 transporters in the kidney offers promise as an attractive weight-neutral approach for treatment of T2DM. Low nanomolar inhibitors contain a glucose residue for targeting which is covalently bound by either a Cor O-glucoside linkage to a large properly oriented hydrophobic planar moiety to increase affinity. The spatial orientation conducive to high affinity differs for O- and C-glucosides. O-Glucosides require vicinal (ortho) substitution, whereas C-glucosides necessitate meta substitution. These agents induce glucosuria, reduce fasting and postprandial hyperglycemia, improve insulin sensitivity, and reduce the need for insulin production. Moreover, the caloric loss induced by SGLT2 inhibition, not surprisingly, was found to produce significant weight loss in animal models, especially if compensatory food consumption was restrained. Although this new class of selective renal glucose reabsorption inhibitors has achieved proof of concept in the clinic, additional studies are necessary to determine whether the metabolic profile and cardiovascular complications of T2DM can be altered with chronic therapy. The C-arylglucoside dapagliflozin 16 is the most advanced SGLT2 inhibitor in clinical trials. 16 is an oral antihyperglycemic agent that rapidly and effectively lowers elevated glucose levels with a minimal risk of hypoglycemia. Furthermore, 16 is a potent and highly selective inhibitor of SGLT2 vs SGLT1, thereby minimizing the potential for gastrointestinal side effects associated with inhibition of intestinal SGLT1. The greater in vivo potency of 16 compared with O-glucosides is attributed in part to the hydrolytic stability conferred by the C-glucoside linkage. Promising short-term clinical studies up to 3 months in patients with T2DM have confirmed that 16 has a pharmacokinetic profile amenable to once-daily dosing and appears generally safe and well tolerated. Treatment of T2DM patients resulted in rapid onset of glucosuria and significant reduction in FSG and PPG resulting in HbA1c reduction after 3 months. Since SGLT2 inhibition induces glucose excretion and consequently increases caloric expenditure, obese individuals as well as those with metabolic syndrome could benefit from this therapy. To date, both the O-glucoside 6b and C-glucoside 16 have produced modest weight loss in T2DM patients in subchronic studies. Large, long-term studies are necessary to establish the safety and efficacy of SGLT2 inhibitors for the treatment of T2DM. Biography William N. Washburn received his Ph.D. in Organic Chemistry in 1971 from Columbia University, studying non-benzenoid aromatic systems with Prof. Ronald Breslow. After completion of a postdoctoral appointment at Harvard University with Prof. E. J. Corey, he became an Assistant Professor in the Department of Chemistry at University of California at Berkeley, addressing
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physical organic and bio-organic problems. He was a member of the Research Laboratories of Eastman Kodak for 12 years before accepting a position with Bristol-Myers Squibb in 1991, where he is currently a Senior Research Fellow. Since joining Bristol-Myers Squibb, Dr. Washburn’s focus has been programs pertaining to obesity and type 2 diabetes.
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