SGLT1/2 (sodium/glucose cotransporter 1/2)

In vitro, LX4211 is a potent dual inhibitor of SGLT1 and SGLT2, with an inhibitory concentration (IC50) of 36 nmol/l against human SGLT1 and 1.8 nmol/l against human SGLT2. [1]

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In vitro activity: LX4211 markedly and significantly improved multiple measures of glycemic control, including fasting plasma glucose, oral glucose tolerance, and HbA(1c); it also significantly decreased serum triglycerides and enhanced urine glucose excretion by inhibiting SGLT2-mediated renal glucose reabsorption. Additionally, LX4211 mediated trends toward decreased blood pressure, weight loss, and increased levels of glucagon-like peptide-1. LX4211 (300 mg) considerably raised glucagon-like peptide-1 and peptide YY levels in comparison to pretreatment values in a follow-up single-dose study involving 12 T2DM patients [1]. This effect was likely caused by delaying SGLT1-mediated intestinal glucose absorption. During the six hours following an oral glucose challenge, mice treated with LX4211 and SGLT1-/- mice likewise exhibited higher GLP-1 AUC values, lower glucose-dependent insulinotropic polypeptide (GIP) AUC values, and reduced blood glucose excursions[2].

To better understand how LX4211 increases GLP-1 and PYY levels, we challenged SGLT1 knockout (-/-) mice, SGLT2-/- mice, and LX4211-treated mice with oral glucose. LX4211-treated mice and SGLT1-/- mice had increased levels of plasma GLP-1, plasma PYY, and intestinal glucose during the 6 hours after a glucose-containing meal, as reflected by area under the curve (AUC) values, whereas SGLT2-/- mice showed no response. LX4211-treated mice and SGLT1-/- mice also had increased GLP-1 AUC values, decreased glucose-dependent insulinotropic polypeptide (GIP) AUC values, and decreased blood glucose excursions during the 6 hours after a challenge with oral glucose alone. However, GLP-1 and GIP levels were not increased in LX4211-treated mice and were decreased in SGLT1-/- mice, 5 minutes after oral glucose, consistent with studies linking decreased intestinal SGLT1 activity with reduced GLP-1 and GIP levels 5 minutes after oral glucose. These data suggest that LX4211 reduces intestinal glucose absorption by inhibiting SGLT1, resulting in net increases in GLP-1 and PYY release and decreases in GIP release and blood glucose excursions. The ability to inhibit both intestinal SGLT1 and renal SGLT2 provides LX4211 with a novel dual mechanism of action for improving glycemic control in patients with T2DM. [2]

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LX4211 (60 mg/kg, p.o.) inhibits SGLT1, which lowers intestinal glucose absorption in mice by increasing net GLP-1 and PYY release and decreasing GIP release and blood glucose excursions. Sotagliflozin (30 mg/kg) considerably enhances glycemic control in nonobese diabetes-prone mice with type 1 diabetes, without raising the frequency of hypoglycemia readings.

Quantitation of LX4211 in plasma. [1]
Blood samples for determining Sotagliflozin (LX4211) plasma concentrations were collected before administration of the dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 h after the dose on days 1, 14, and 28. Additional blood samples were collected immediately before dosing on days 7 and 21, and a single sample was collected on day 36. Immediately after collection, the blood samples were placed in an ice/water bath; plasma was then separated by centrifugation at 2,000g for 15 min at 4 °C. Within 90 min of collection, plasma samples were stored at −70 °C. Plasma LX4211 levels were quantitated using liquid chromatography with tandem mass spectrometric detection. [1]

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Sotagliflozin (LX4211) decreases postprandial glucose excursions by inhibiting intestinal sodium/glucose cotransporter 1 (SGLT1) and increases urinary glucose excretion (UGE) by inhibiting renal SGLT2. In clinical studies of patients with T2DM, LX4211 appears to act through dual SGLT1/SGLT2 inhibition to improve glycemic control and promote weight loss. Here, researchers present preclinical studies that explored the ability of LX4211 to improve glycemic control and promote weight loss. Researchers found that 1) LX4211 inhibited in vitro glucose transport mediated by mouse, rat, and dog SGLT1 and SGLT2 [3].

LX4211 has been shown to inhibit glucose transport by HEK293 cells overexpressing mouse or human SGLT1 or SGLT2. As shown in Table 1, LX4211 also inhibits glucose transport mediated by rat and dog SGLT1 and SGLT2 [3].

The patients were randomly and equally assigned to receive either 150 mg or 300 mg of Sotagliflozin (LX4211) or placebo, once daily for 28 days. The methods used to generate and implement the random allocation sequence, and to blind and unblind the study, are described in the Supplementary Materials and Methods online. For this proof-of-concept study in patients with T2DM, 12 patients were assigned to each group; no formal sample size calculation was made. Both active drug and placebo were administered as oral solutions at 8:00 AM, 1 h before breakfast; the placebo was composed of identical ingredients except that it lacked Sotagliflozin (LX4211). Doses were selected based on the earlier observation that the 300-mg dose was well tolerated and produced a maximal glycosuric effect in healthy volunteers enrolled in a phase I trial (data not shown). The inpatient active treatment interval of 28 days was followed by 7 days of outpatient follow-up and end-of-study sample collection. The primary objective was to establish the safety profile for the two doses of Sotagliflozin (LX4211) in patients with T2DM. The secondary objective was to evaluate the efficacy of the two LX4211 doses as compared with placebo, using the following measures: UGE, response to OGTT, FPG, fructosamine levels, homeostatic model assessment of insulin resistance, 2-h PPG, and LX4211 pharmacokinetics. [1]

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Dissolved in aqueous 0.1% v/v Tween 80; 60 mg/kg; oral administration.

Male albino C57BL/6-Tyrc-Brd mice

Absorption, Distribution and Excretion
Following a single dose, the Tmax of sotagliflozin ranged from 1.25 to 3 hours. Following multiple doses, the Tmax ranged from 2.5 to 4 hours. The estimated oral bioavailability of sotagliflozin is 71%.
Sotagliflozin is primarily eliminated via the renal route, with 57% of administered drug material appearing in the urine and 37% appearing in the feces.
Sotagliflozin has a mean apparent volume of distribution of 9392 L.
In healthy volunteers, the mean apparent clearance of sotagliflozin ranged from 261 to 374 L/h. The mean apparent clearance estimated in a population of mostly type 1 diabetic patients was 239 L/h.

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Metabolism / Metabolites
The major metabolite of sotagliflozin is a 3-O-glucuronide (M19), which comprised ~94% of of the radioactivity in plasma following the oral administration of a radiolabeled dose of sotagliflozin. The M19 metabolite is effectively inactive, with >275-fold less activity at SGLT1 and SGLT2 compared to the parent drug. The primary route of metabolism is via glucuronidation by UGT1A9 (and both UGT1A1 and UGT2B7, to a lesser extent) as well as oxidation via CYP3A4.

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Biological Half-Life
The mean terminal half-life of sotagliflozin ranged from 21 to 35 hours and from 19 to 26 hours for its M19 metabolite.

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Pharmacokinetic parameters and mean plasma concentration–time profiles are summarized in Table 4. For each LX4211 dose, plasma concentrations were detected within 15 min, increased with increasing dose, and decreased in a biphasic pattern. The maximum plasma LX4211 concentration (Cmax) appeared at 0.5–2.0 h after dosing, and ranged from 82.5–115 ng/ml and 230–307 ng/ml in the 150-mg and 300-mg dose groups, respectively. The increases in Cmax and AUC for plasma concentration over time curve were slightly more than dose-proportional. The median time to reach Cmax (i.e., tmax) was similar on days 14 and 28 for the two dose groups (1.00–1.50 h), with individual values ranging from 0.48 to 2.02 h. Mean plasma LX4211 concentrations at the end of the dosage interval (Cmin) were similar on days 7, 14, 21, and 28, and all were higher than values on day 1, in both the 150- and 300-mg dose groups (Table 4; Supplementary Table S11 online). Cmax and AUC0–tau values, as determined on days 1, 14, and 28, were similar on days 14 and 28, and each was higher than values on day 1 in both dose groups. Collectively, these data support the view that steady state was reached by day 14, and possibly even by day 7, based on the Cmin value. Apparent total clearance of LX4211 from plasma after oral administration (CL/F) and CL/F at steady state (CL/Fss) were similar across dose groups. After multiple doses, CL/Fss was lower on days 14 and 28 than the value observed after a single dose. CL/F on day 1 and CL/Fss on days 14 and 28 were higher than the sum of hepatic blood flow and renal blood flow, suggesting the possibility of unabsorbed LX4211 in the gastrointestinal tract. Mean ± SD values for t1/2 (half-life) were 20.7 ± 13.7 and 13.5 ± 5.3 h in the 150-mg and 300-mg dose groups, respectively. [1]

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The pharmacokinetic parameters derived for plasma LX4211 are summarized in Table 5. The absorption rate for the LX4211 liquid formulation was approximately threefold faster than for the tablets, with the median Tmax being 3.00 h for each tablet treatment group and 0.875 h for the liquid treatment group (Figure 2f). Also, the mean Cmax was 2- to 2.5-fold lower for the tablet treatments than for the liquid formulation. Although the AUC values associated with each tablet treatment group were similar, both were lower than that of the liquid formulation; this finding suggests that the tablet formulation has lower bioavailability. The mean ± SD values for t1/2 were 13.2 ± 2.8, 19.8 ± 8.8, and 17.9 ± 9.0 h for the 2 × 150-mg tablets, 6 × 50-mg tablets, and liquid formulation, respectively, consistent with once-daily dosing of LX4211. [1]

Protein Binding
Both sotagliflozin and its major metabolite, M19, are extensively (~98%) protein-bound in plasma, although the specific protein(s) to which they bind have not been elucidated.

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Sotagliflozin exerts its pharmacologic effects by slowing glucose absorption in the gastrointestinal tract and increasing the excretion of glucose in the urine. It is administered by mouth once daily before the first meal of the day. The use of SGLT2 inhibitors, including sotagliflozin, can cause diabetic ketoacidosis (DKA). Patients, especially those with a higher baseline risk of DKA, should be instructed on how and when to monitor for ketoacidosis and what actions to take when DKA is suspected. SGLT2 inhibitors, including sotagliflozin, also increase the risk of genital infections. This is due to the increase in urinary glucose excretion, which provides a relatively glucose-rich environment in which infectious agents may establish themselves.

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LX4211 was safe and well tolerated at the doses and schedule employed. There were no treatment-emergent urinary tract infections, genital infections, CV events, or episodes of hypoglycemia, and laboratory data provided no evidence of renal toxicity. Importantly, gastrointestinal AEs were mild and equally divided among the LX4211 and placebo groups. Serum magnesium rose slightly with LX4211 treatment but remained within the normal range, as was observed with dapagliflozin,15 and urinary calcium excretion did not increase in LX4211-treated patients.[1]

[1]. LX4211, a dual SGLT1/SGLT2 inhibitor, improved glycemic control in patients with type 2 diabetes in a randomized, placebo-controlled trial. Clin Pharmacol Ther. 2012 Aug;92(2):158-69.

[2]. LX4211 increases serum glucagon-like peptide 1 and peptide YY levels by reducing sodium/glucose cotransporter 1 (SGLT1)-mediated absorption of intestinal glucose. J Pharmacol Exp Ther. 2013 May;345(2):250-9.

[3]. Effect of LX4211 on glucose homeostasis and body composition in preclinical models. J Pharmacol Exp Ther . 2014 Aug;350(2):232-42.

Sotagliflozin is an S-glycosyl compound that is 1-thio-beta-L-xylopyranose in which the anomeric hydroxy group is replaced by a 4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl group and the thiol is replaced by a methylsulfanediyl group. It is an inhibitor of SGLT1 and SGLT2 that is approved to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with heart failure or type 2 diabetes mellitus, chronic kidney disease, and other cardiovascular risk. It has a role as a sodium-glucose transport protein subtype 2 inhibitor, a hypoglycemic agent, an antihypertensive agent, a cardioprotective agent and a sodium-glucose transport protein subtype 1 inhibitor. It is a C-glycosyl compound, an aromatic ether, a member of monochlorobenzenes and a S-glycosyl compound.
Sotagliflozin is a dual inhibitor of SGLT1 and SGLT2, the first of its kind, which is approved for use in the EU, in combination with insulin, to improve glycemic control in patients with type 1 diabetes mellitus (T1DM) and a BMI ≥27 kg/m2. Its potency in inhibiting SGLT2 is similar to that of other SGLT2 inhibitors, such as [canagliflozin] and [dapagliflozin], but its potency in inhibiting SGLT1 is >10-fold higher than its predecessors. The added inhibition of intestinal SGLT1 delays glucose absorption in the distal small intestine and colon, thereby reducing post-prandial glucose levels. Sotagliflozin was approved by the EMA under the brand name "Zynquista" on April 26, 2019, for the treatment of type 1 diabetes. A similar approval has also been sought in the US, but the FDA has since published a proposal to refuse the approval because the data submitted did not show that it was safe under the proposed conditions of use. On March 22, 2022, the marketing authorization of sotagliflozin for the treatment of type 1 diabetes mellitus was withdrawn by the EMA due to commercial reasons. In May 2023, sotagliflozin was approved by the FDA to reduce the risk of cardiovascular death and heart failure in patients with high risk factors.[]
Sotagliflozin is a Sodium-Glucose Cotransporter 2 Inhibitor. The mechanism of action of sotagliflozin is as a Sodium-Glucose Transporter 2 Inhibitor, and P-Glycoprotein Inhibitor.
Sotagliflozin is an orally bioavailable inhibitor of the sodium-glucose co-transporter subtype 1 (SGLT1) and 2 (SGLT2), with potential antihyperglycemic activity. Upon oral administration, sotagliflozin binds to and blocks both SGLT1 in the gastrointestinal (GI) tract and SGLT2 in the kidneys, thereby suppressing the absorption of glucose from the GI tract and the reabsorption of glucose by the proximal tubule into the bloodstream, respectively. This decreases glucose uptake and enhances the urinary excretion of glucose, which lowers and/or normalizes blood glucose levels. SGLT1 is the primary transporter responsible for glucose absorption from the GI tract. SGLT2, a transport protein exclusively expressed in the proximal renal tubules, mediates approximately 90% of renal glucose reabsorption from tubular fluid.

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Drug Indication
In the US, sotagliflozin is indicated to reduce the risk of cardiovascular death and heart failure in adults with heart failure, type 2 diabetes mellitus, chronic kidney disease, and other cardiovascular risk factors.
Zynquista is indicated as an adjunct to insulin therapy to improve glycaemic control in adults with type 1 diabetes mellitus with a Body Mass Index (BMI) ≥ 27 kg/m2, who have failed to achieve adequate glycaemic control despite optimal insulin therapy. ,
Treatment of type I diabetes mellitus
Treatment of type II diabetes mellitus

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Mechanism of Action
Sodium-glucose co-transporter types 1 and 2 (SGLT1 and SGLT2) are integral in the transport of glucose in the body. SGLT1 is the major transporter for glucose absorption in the gastrointestinal tract, while SGLT2 is the predominant transporter responsible for reabsorption of glucose in the glomerulus. Sotagliflozin is a dual inhibitor of both SGLT1 and SGLT2. Inhibition of SGLT1 results in a delay in glucose absorption and a blunting of postprandial hyperglycemia, while inhibition of SGLT2 reduces renal reabsorption of filtered glucose, thereby increasing urinary glucose excretion.

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Thirty-six patients with type 2 diabetes mellitus (T2DM) were randomized 1:1:1 to receive a once-daily oral dose of placebo or 150 or 300 mg of the dual SGLT1/SGLT2 inhibitor LX4211 for 28 days. Relative to placebo, LX4211 enhanced urinary glucose excretion by inhibiting SGLT2-mediated renal glucose reabsorption; markedly and significantly improved multiple measures of glycemic control, including fasting plasma glucose, oral glucose tolerance, and HbA(1c); and significantly lowered serum triglycerides. LX4211 also mediated trends for lower weight, lower blood pressure, and higher glucagon-like peptide-1 levels. In a follow-up single-dose study in 12 patients with T2DM, LX4211 (300 mg) significantly increased glucagon-like peptide-1 and peptide YY levels relative to pretreatment values, probably by delaying SGLT1-mediated intestinal glucose absorption. In both studies, LX4211 was well tolerated without evidence of increased gastrointestinal side effects. These data support further study of LX4211-mediated dual SGLT1/SGLT2 inhibition as a novel mechanism of action in the treatment of T2DM.[1]

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Treatments that lower blood glucose levels and body weight should benefit patients with type 2 diabetes mellitus (T2DM). We developed LX4211 [(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol], an orally available small molecule that decreases postprandial glucose excursions by inhibiting intestinal sodium/glucose cotransporter 1 (SGLT1) and increases urinary glucose excretion (UGE) by inhibiting renal SGLT2. In clinical studies of patients with T2DM, LX4211 appears to act through dual SGLT1/SGLT2 inhibition to improve glycemic control and promote weight loss. Here, we present preclinical studies that explored the ability of LX4211 to improve glycemic control and promote weight loss. We found that 1) LX4211 inhibited in vitro glucose transport mediated by mouse, rat, and dog SGLT1 and SGLT2; 2) a single daily LX4211 dose markedly increased UGE for >24 hours in mice, rats, and dogs; and 3) in the KK.Cg-Ay/J heterozygous (KKA(y)) mouse model of T2DM, LX4211 lowered A1C and postprandial glucose concentrations while increasing postprandial glucagon-like peptide 1 concentrations. Also, long-term LX4211 treatment 1) decreased oral glucose tolerance test (OGTT) glucose excursions, increased OGTT 30-minute insulin concentrations and increased pancreatic insulin content in KKA(y) mice; and 2) decreased weight gain in dogs and rats but not in KKA(y) mice while increasing food consumption in dogs, rats, and KKA(y) mice; in these KKA(y) mice, calories lost through UGE were completely offset by calories gained through hyperphagia. These findings suggest that LX4211 improves glycemic control by dual SGLT1/SGLT2 inhibition in mice as in humans, and that the LX4211-mediated weight loss observed in patients with T2DM may be attenuated by LX4211-mediated hyperphagia in some of these individuals.[3]

C21H25CLO5S

424.94

424.111

C, 59.36; H, 5.93; Cl, 8.34; O, 18.83; S, 7.55

1018899-04-1

24831714

White to off-white solid powder

1.4±0.1 g/cm3

607.9±55.0 °C at 760 mmHg

321.4±31.5 °C

0.0±1.8 mmHg at 25°C

1.642

5.63

3

6

6

28

476

5

ClC1C([H])=C([H])C(=C([H])C=1C([H])([H])C1C([H])=C([H])C(=C([H])C=1[H])OC([H])([H])C([H])([H])[H])[C@@]1([H])[C@@]([H])([C@]([H])([C@@]([H])([C@]([H])(O1)SC([H])([H])[H])O[H])O[H])O[H]

QKDRXGFQVGOQKS-CRSSMBPESA-N

InChI=1S/C21H25ClO5S/c1-3-26-15-7-4-12(5-8-15)10-14-11-13(6-9-16(14)22)20-18(24)17(23)19(25)21(27-20)28-2/h4-9,11,17-21,23-25H,3,10H2,1-2H3/t17-,18-,19+,20+,21-/m1/s1

(2S,3R,4R,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-methylsulfanyloxane-3,4,5-triol

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.88 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.88 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)