Empagliflozin | Sodium-Glucose Co-Transporter 2 Inhibitor | SGLT2 Inhibitor I Treatment for Type 2 Diabetes Mellitus

Empagliflozin [1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yl-oxy)-benzyl]-benzene] is an oral, potent and selective inhibitor of sodium-glucose co-transporter 2 (SGLT2). Oral Empagliflozin is a convenient once-daily treatment for adult patients with type 2 diabetes mellitus (T2DM) [1, 2].

Empagliflozin showed greater than 2500-fold selectivity for hSGLT-2 over hSGLT-1 (IC₅₀ = 8300 nM) and more than 3500-fold selectivity over hSGLT-4 (IC₅₀ = 11000 nM) [3].

Empagliflozin: 2D and 3D Structure

In several phase III trials (typically 24 weeks or more duration) and extension studies (typically more than 76 weeks’ treatment), Empagliflozin monotherapy or add-on therapy to other anti-hyperglycaemics, including insulin, improved glycaemic control and reduced bodyweight and systolic blood pressure in adult patients with type 2 diabetes. As add-on therapy to metformin, Empagliflozin driven improvement in glycaemic control is noninferior to glimepiride at 52 weeks but superior to glimepiride at 104 weeks. Empagliflozin was well tolerated by participants in these clinical trials, with most adverse events being mild or moderate in intensity. 

Empagliflozin was approved in Europe in May 2014 and was approved by the FDA in August 2014 as once-daily oral tablet for adults with type 2 diabetes.

Empagliflozin Synthesis

Org Lett 2014, 16(16), 4090-4093: An efficient production synthesis of the SGLT-2 inhibitor Empagliflozin from 5-iodo-2-chlorobenzoic acid is described. The key tactical stage involves I/Mg exchange of aryl iodide followed by addition to glucono lactone in THF. Subsequent in situ treatment of the resulting lactol with HCl in MeOH produces β-anomeric methyl glycopyranoside which is, without isolation, directly reduced with Et₃SiH mediated by AlCl₃ as a Lewis acid in CH₂Cl₂/MeCN to afford Empagliflozin in 50% overall yield. The process was implemented for production on a metric ton scale for commercial launch. Also see Ref. 5.

Identifications:

1H NMR (Estimated) for Empagliflozin

Experimental: ¹H NMR (400 MHz, DMSO-d₆) 7.70 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.24 (dd, J = 2.0, 8.4 Hz, 1H), 7.17 (ABq, J = 8.8 Hz, 2H), 6.82 (ABq, J = 8.8 Hz, 1H), 4.95 (m, 3H), 4.84 (d, J = 6.4 Hz, 1H), 4.46 (t, J = 6.0 Hz, 1H), 3.98 (m, 3H), 3.87-3.67 (m, 5H), 3.46-3.42 (m, 1H), 3.27-3.10 (m, 4H), 2.23-2.14 (m, 1H), 1.96-1.89 (m, 1H).

13C NMR (Estimated) for Empagliflozin

Experimental: ¹³C NMR (400 MHz, DMSO-d₆) δ 155.4, 139.6, 137.7, 131.9, 131.5, 130.9, 129.6, 128.6, 127.4, 115.1, 81.2, 80.6, 78.2, 76.9, 74.7, 72.2, 70.3, 66.4, 61.3, 37.5, 32.4.

References:

1. McGill, J. B. The SGLT2 Inhibitor Empagliflozin for the Treatment of Type 2 Diabetes Mellitus: a Bench to Bedside Review. Diabetes Ther 2014, 5(1), 43-63. (free article)

2. Scott, L. J. Empagliflozin: A Review of Its Use in Patients with Type 2 Diabetes Mellitus. Drugs 2014, 74, 1769-1784. (FMO only)

3. Grempler, R.; et. al. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes Metab 2012, 14(1), 83-90. (FMO only) (an excellent work published.)

4. Wang, X. J.; et. al. Efficient synthesis of Empagliflozin, an inhibitor of SGLT-2, utilizing an AlCl3-promoted silane reduction of a ß-glycopyranoside. Org Lett 2014, 16(16), 4090-4093. (FMO only)
5. Himmelsbach, F.; et. al. Glucopyranosyl-substituted benzol derivatives, drugs containing said compounds, the use thereof and method for the production thereof. WO2005092877A1

Luseogliflozin I Sodium Glucose Co-transporter 2 Inhibitor I Treatment for Diabetes Mellitus

Luseogliflozin [(2S,3R,4R,5S,6R)-2-{5-[(4-ethoxyphenyl)methyl]-2-methoxy-4-methylphenyl}- 6-(hydroxymethyl)thiane-3,4,5-triol hydrate] is an oral, 1-thio-D-glucitol derivative Sodium glucose co-transporter 2 (SGLT2) inhibitor that is developed for the treatment of type 2 diabetes mellitus (T2DM).

Luseogliflozin is a potent and selective SGLT2 inhibitor, with a 50% inhibitory concentration (IC₅₀) of 2.26 nM, which is 1765 times lower than its IC₅₀ for SGLT1 (IC₅₀ = 3990 nM). This potency allows the administration of lower doses of Luseogliflozin compared with other SGLT2 inhibitors for the treatment of T2DM.

Luseogliflozin: 2D and 3D Structure

Luseogliflozin an orally active second-generation SGLT2 inhibitor is developed for the treatment of patients with type 2 diabetes mellitus (T2DM). In March 2014, the drug received its first global approval for this indication in Japan, either as monotherapy or in combination with other antihyperglycaemic agents.

Diabetes and SGLT Inhibitors

Good control of blood glucose can be achieved by a controlled diet and physical exercise. Diabetes is associated with an increased risk of both macrovascular (cardiovascular disease) and microvascular (nephropathy, retinopathy, and neuropathy) complications. Diabetes can also be managed by orally active drugs including sulfonylurea, biganide etcs.

Sodium-dependent glucose transporters (SGLTs) present on the chronic membrane of the intestine and kidney play an important role in the absorption and reabsorption of glucose. Inhibition of renal glucose reabsorption is emerging as a novel therapy for patients with type 2 diabetes mellitus (T2DM).

In particular, blocking the sodium-glucose cotransporter 2 (SGLT2)-a low-affinity high-capacity transporter localised to the renal proximal tubules-has been shown to suppress glucose reabsorption, leading to increased urinary excretion with a concomitant reduction in plasma glucose levels. Compounds selective for SGLT2 are desirable as SGLT1 is highly expressed in the gastrointestinal tract but only moderately expressed in the kidneys.

SGLT2 inhibitors have an insulin-independent mechanism of action; these drugs are expected to improve glycemic control with a low risk of major hypoglycemic events. Furthermore, total calorie loss through urinary glucose excretion may not cause weight gain and may even achieve weight loss.

Dosages and Approvals:

Luseogliflozin [Tradename: Lusefi] is a selective SGLT2 inhibitor, which received its first marketing approval in Japan for the treatment of T2DM on the 24^th of March 2014. The drug has received approval as 2.5 and 5 mg oral tablets with a recommended starting dose of 2.5 mg once daily. This may be increased to 5 mg once daily if necessary for optimal clinical effect.

Luseogliflozin is manufactured by Taisho Pharmaceutical, Japan and co-marketed by both Taisho and Novartis in Japan. Novartis licensed the marketing rights for Luseogliflozin in Japan. Under the terms of this agreement, Taisho will receive an upfront payment and milestone payments from Novartis.

Luseogliflozin Synthesis

J Med Chem 2010, 53(8), 3247-3261:

Final Synthesis:

Identifications:

1H NMR (Estimated) for Luseogliflozin

References:

1. Markham, A.; et. al. Luseogliflozin: first global approval. Drugs 2014, 74(8), 945-50. (FMO only)

2. Seino, Y. Luseogliflozin for the treatment of type 2 diabetes. Expert Opin Pharmacother 2014, 15(18), 2741-9. (FMO only)

3. Yamamoto, K.; et. al. TS-071 is a novel, potent and selective renal sodium-glucose cotransporter 2 (SGLT2) inhibitor with anti-hyperglycaemic activity. Br J Pharmacol 2011, 164(1), 181-91. (Free copy)
4. Kakinuma, H.; et. al. (1S)-1,5-Anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-D-glucitol (TS-071) is a Potent, Selective Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for Type 2 Diabetes Treatment. J Med Chem 2010, 53(8), 3247-3261. (FMO only)

Drugs in Clinical Pipeline: SHR3824

SHR3824 [(1R,2S,3S,4R,5R)-5-(4-Chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1] octane-2,3,4-triol] is a novel, oral and selective SGLT2 inhibitor, which is structurally different from other SGLT2 inhibitors (flozins) that are currently available or in the late stages of clinical development.

In vitro, SHR3824 potently inhibits human SGLT2, but exerts much weak inhibition on human SGLT1 (IC₅₀ hSGLT2, hSGLT1 = 2.38 and 4324 nM, respectively) showing a selectivity of 1817 for SGLT2. Acute oral administration of SHR3824 (0.3, 1.0, 3.0 mg/kg) dose-dependently improved glucose tolerance in ICR mice, and reduced hyperglycemia by increasing urinary glucose excretion in GK rats and db/db mice. Chronic oral administration of SHR3824 (0.3, 1.0, 3.0 mg/kg.d) dose-dependently reduced blood glucose and HbA1c levels in GK rats and db/db mice, and significantly increased insulin-stimulated glucose uptake in the soleus muscles and enhanced insulin staining in the islet cells of db/db mice [1].

SHR3824 is discovered by Shanghai Hengrui Pharmaceuticals Co, Ltd, (Shanghai) and is currently in Phase I clinical studies in China  for treatment of type 2 diabetes (T2DM).

References:
1. Yan, P. K.; et. al. SHR3824, a novel selective inhibitor of renal sodium glucose cotransporter 2, exhibits antidiabetic efficacy in rodent models. Acta Pharmacol Sin 2014, 35(5), 613-624.

Drugs in Clinical Pipeline: LIK066

LIK066 [(2S,3R,4R,5S,6R)-2-(3-((2,3- dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-4-ethylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, (S)-Pyrrolidine-2-carboxylic acid (2:1)] is an orally available, potent dual inhibitor of sodium-glucose transporter-1 (SGLT1) and sodium-glucose transporter-2 (SGLT2), with an in vivo inhibitory concentration (IC₅₀) of 22.0 nM against human SGLT1 and 0.5 nM against human SGLT2 [1, 2].

References:

1. Opinion of the Paediatric Committee on the agreement of a Paediatric Investigation Plan and a deferral and a waiver. 2014, EMEA-001527-PIP01-13 (here) [ Novartis revealed the IUPAC name here].

2. Bebernitz, G. R. Glycoside derivatives and their uses for the treatment of diabetes. WO2012140597A1 (synthesis and activity)

Drugs in Clinical Pipeline: Sotagliflozin

Sotagliflozin [(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol] is an orally available, potent dual inhibitor of sodium-glucose transporter-1 (SGLT1) and sodium-glucose transporter-2 (SGLT2), with an in vivo inhibitory concentration (IC₅₀) of 36 nM against human SGLT1 and 1.8 nM against human SGLT2.

Drugs in Clinical Pipeline: Bexagliflozin

Bexagliflozin [(2S,3R,4R,5S,6R)-2-[4-chloro-3-({4-[2-(cyclopropyloxy) ethoxy] phenyl} methyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol] is an orally administered drug for the treatment of Type 2 Diabetes Mellitus (T2DM) and is classified as a Sodium Glucose co-Transporter 2 (SGLT2) Inhibitor.   Bexagliflozin exhibited an IC₅₀ of 2 nM with a 2435-fold selectivity ratio against SGLT2 compared to SGLT1.

Chemically, Bexagliflozin falls in the C-aryl glucoside class and synthesized via EGT1474 [1, 2]. EGT1474 is the co-crystalline form of Bexagliflozin with L-proline in 1:2 stoichiometry. The mass ratio of EGT1474 to Bexagliflozin is 1.5:1 [1, 2]. Bexagliflozin is in Phase 2b study to evaluate the effect of bexagliflozin tablets in subjects with type 2 diabetes mellitus.

The inhibitory effects of Bexagliflozin for human SGLT1 and SGLT2 were evaluated in an AMG uptake assay and the in vivo efficacy of treatment with Bexagliflozin was investigated in rats and dogs after a single dose and in db/db mice after chronic administration. The IC₅₀ values for Bexagliflozin against human SGLT1 and SGLT2 are 5.6 uM and 2 nM, respectively. In normal rats and dogs a saturable urinary glucose excretion was produced with an ED₅₀ of 0.38 and 0.09 mg/kg, respectively. Following chronic administration to db/db mice, Bexagliflozin dose-dependently reduced HbA1c and blood glucose concentration without affecting body mass or insulin level. Additionally, Bexagliflozin significantly prolonged the median survival of SHRSP rats [1].

The activity of Bexagliflozin is as follows:

IC₅₀ (Human SGLT1 Activity, AMG Uptake Assay) =  5.6 ± 0.59 uM
IC₅₀ (Human SGLT2 Activity, AMG Uptake Assay) =  0.002 ± 0.001 uM

The activity of EGT1474 is as follows:

IC₅₀ (Human SGLT1 Activity, AMG Uptake Assay) =  6.8 ± 0.47 uM
IC₅₀ (Human SGLT2 Activity, AMG Uptake Assay) =  0.003 ± 0.001 uM

Common Name: Bexagliflozin
Synonym: THR1442; THR-1442, EGT0001442; EGT1442
CAS Number: 1118567-05-7

IUPAC Name: (2S,3R,4R,5S,6R)-2-[4-chloro-3-({4-[2-(cyclopropyloxy)ethoxy]phenyl} methyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H- pyran-3,4,5-triol

SMILES:c1cc(ccc1Cc2cc(ccc2Cl)[C@H]3[C@@H]([C@H]([C@@H]([C@H](O3)CO)O)O)O) OCCOC4CC4
Mechanism of Action: SGLT2 Inhibitor; Sodium Glucose co-Transporter 2 Inhibitor
Indication: Treatment of Type 2 Diabetes; Treatment of T2DM
Development Stage: Phase II
Originator: Egret Pharma (Shanghai)\Theracos Inc.

The sodium-dependent (“active”) glucose cotransporters (SGLTs), including SGLT1 (found predominantly in the intestinal brush border) and SGLT2 (localized in the renal proximal tubule), are being considered as therpeutic targets. In particular, SGLT2 has been found to be responsible for the majority of glucose reuptake by the kidneys Inhibition of renal SGLT is now considered a useful approach to treating hyperglycemia by increasing the amount of glucose excreted in the urine. The potential of this therapeutic approach is further supported by recent findings that mutations in the SGLT2 gene occur in cases of familial renal glucosuria, an apparently benign syndrome characterized by urinary glucose excretion in the presence of normal serum glucose levels and the absence of general renal dysfunction or other disease.

Therefore, compounds which inhibit SGLT, particularly SGLT2, are promising candidates for use as antidiabetic drugs. In addition, since cancer cells show increased glucose uptake in comparison to their normal counterparts, SGLT inhibition has been proposed as a method for treating cancer by starving cancer cells. For example, studies suggest that SGLT2 plays a role in glucose uptake in metastatic lesions of lung cancer. Thus, SGLT2 inhibitors may also be useful as anticancer agents [2].

Plasma insulin levels were not affected by the administration of Bexagliflozin to diabetic animals, which indicates that the blood glucose lowering effect of Bexagliflozin does not rely on insulin secretion or insulin action. Thus, agents of this class could be effective in a wide variety of patients.

Bexagliflozin increases urinary glucose excretion in healthy rats and dogs. A sustained effect in reducing blood glucose concentration and HbA1c level was demonstrated in diabetic mice. No body weight gain, stimulation of insulin secretion or GI effects were observed during the study in diabetic mice, suggesting that Bexagliflozin has low risk for provoking the weight gain, hypoglycemia or diarrhea often elicited by current anti-diabetic medications. Further, treatment with Bexagliflozin significantly prolonged the survival of SHRSP rats on a stroke-promoting diet. Therefore, Bexagliflozin may provide an efficacious treatment strategy for patients with the comorbidities of diabetes and hypertension [1].

References:

1. Wang, Y.-X.; et. al. EGT1442, a potent and selective SGLT2 inhibitor, attenuates blood glucose and HbA1c levels in db/db mice and prolongs the survival of stroke-prone rats. Pharmacol Res 2011, 63(4), 284-293.

2. Xu, B.; et. al. Process for the preparation of benzylbenzene sglt2 inhibitors. US20130267694A1

3. ClinicalTrials.gov A Dose Range Finding Study to Evaluate the Effect of Bexagliflozin Tablets in Subjects With Type 2 Diabetes Mellitus. NCT02390050 (retrieved on 26-03-2015).

4. ClinicalTrials.gov Safety and Efficacy Study of EGT0001442 in Subjects With Type 2 Diabetes Mellitus. NCT01029704 (retrieved on 26-03-2015).

5. ClinicalTrials.gov Efficacy and Safety of EGT0001442 in Patients With Type 2 Diabetes Mellitus. NCT01377844  (retrieved on 26-03-2015).