Discovery of LX2761, a Sodium-Dependent Glucose Cotransporter 1 (SGLT1) Inhibitor Restricted to the Intestinal Lumen, for the Treatment of Diabetes

Goodwin, Nicole C.; Ding, Zhi‐Ming; Harrison, Bryce A.; Strobel, Eric D.; Harris, Angela L.; Smith, Melinda; Thompson, Andrea Y.; Xiong, Wendy; Mseeh, Faika; Bruce, Debra; Diaz, Damaris; Gopinathan, Suma; Li, Ling; O’Neill, Emily; Thiel, M. van; Wilson, Alan G. E.; Carson, Kenneth G.; Powell, David R.; Rawlins, David B.

doi:10.1021/acs.jmedchem.6b01541

Cited by 54 publications

(47 citation statements)

References 52 publications

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“…Current clinical trials are investigating the use of mizagliflozin as a potential candidate to improve functional constipation (due to its ability to increase luminal glucose and water content) . In addition, newly developed non‐absorbable SGLT1 inhibitors include LX2761 and TP0438836 (Table ). Both compounds significantly reduced blood glucose excursions in response to oral glucose tolerance tests in rodents.…”

Section: Development Of Sglt Inhibitorsmentioning

confidence: 99%

“…Inevitably, blocking glucose transport in the upper small intestine will lead to a greater glucose delivery to further distal segments of the small intestine and colon . It has been speculated that the gut microbiome metabolizes glucose in the colon to form SCFA, which bind to free fatty acid receptors (FFAR2/3) on distal small intestine L cells and may promote sustained GLP‐1 release.…”

Section: Intestinal Sglt1 Inhibition: What Does It Add?mentioning

confidence: 99%

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What does sodium‐glucose co‐transporter 1 inhibition add: Prospects for dual inhibition

Rieg

2019

Diabetes Obesity Metabolism

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Epithelial glucose transport is accomplished by Na + -glucose co-transporters, SGLT1 and SGLT2.In the intestine, uptake of dietary glucose is for its majority mediated by SGLT1, and humans with mutations in the SGLT1 gene show glucose/galactose malabsorption. In the kidney, both transporters, SGLT1 and SGLT2, are expressed and recent studies identified that SGLT2 mediates up to 97% of glucose reabsorption. Humans with mutations in the SGLT2 gene show familial renal glucosuria. In the last three decades, significant progress was made in understanding the physiology of these transporters and their potential as therapeutic targets. Based on the structure of phlorizin, a natural compound acting as a SGLT1/2 inhibitor, initially several SGLT2, and later SGLT1 and dual SGLT1/2 inhibitors have been developed. Interestingly, SGLT2 knockout or treatment with SGLT2 selective inhibitors only causes a fractional glucose excretion in the magnitude of $60%, an effect mediated by up-regulation of renal SGLT1. Based on these findings the hypothesis was brought forward that dual SGLT1/2 inhibition might further improve glycaemic control via targeting two distinct organs that express SGLT1: the intestine and the kidney. Of note, SGLT1/2 double knockout mice completely lack renal glucose reabsorption. This review will address the rationale for the development of SGLT1 and dual SGLT1/2 inhibitors and potential benefits compared to sole SGLT2 inhibition. K E Y W O R D Schronic kidney disease, drug development, heart failure, inhibitor, intestinal glucose transport, renal glucose transport, sodium-glucose cotransporter, type 1 diabetes, type 2 diabetes

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Section: Development Of Sglt Inhibitorsmentioning

confidence: 99%

Section: Intestinal Sglt1 Inhibition: What Does It Add?mentioning

confidence: 99%

What does sodium‐glucose co‐transporter 1 inhibition add: Prospects for dual inhibition

Rieg

2019

Diabetes Obesity Metabolism

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“…In this context, the development of straightforward, modular,a nd operationally simple conditions to access Carylated saccharides remains an unsolved challenge,a nd methods that would preserve the anomeric carbon to afford non-classical, "reverse aryl C-glycosides" are particularly scarce.I ndeed, despite the attractive biological properties of these compounds, [11] few synthetic efforts have been carried out in this regard. [12] Other approaches toward the synthesis of reverse aryl Cglycosides have been reported, such as the [4+ +2] cycloaddition between Danishefskysd ienes and aromatic aldehydes,y ielding glycal derivatives, [13] or the addition of organozinc reagents to 4a-epoxypyranosides (Scheme 2).…”

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confidence: 99%

Synthesis of Non‐Classical Arylated C‐Saccharides through Nickel/Photoredox Dual Catalysis

et al. 2018

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The development of synthetic tools to introduce saccharide derivatives into functionally complex molecules is of great interest, particularly in the field of drug discovery. Herein, we report a new route toward highly functionalized, arylated saccharides, which involves nickel-catalyzed cross-coupling of photoredox-generated saccharyl radicals with a range of aryl- and heteroaryl bromides, triggered by an organic photocatalyst. In contrast to existing methods, the mild reaction conditions achieve arylation of saccharide motifs while leaving the anomeric carbon available, thus providing access to a class of arylated glycosides that has been underexplored until now. To demonstrate the potential of this strategy in late-stage functionalization, a variety of structurally complex molecules incorporating saccharide moieties were synthesized.

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“…We are developing LX2761, a compound restricted to the intestinal lumen where it inhibits SGLT1, to provide a therapeutic option for people with diabetes that improves their glycemic control with minimal systemic side effects and adequate gastrointestinal tolerability. In our initial report (Goodwin et al, 2017), we showed that LX2761 inhibits SGLT1 and SGLT2 with IC 50 values of 2.2 and 2.7 nM, respectively. Consistent with being designed to have poor oral bioavailability, LX2761 had extremely low systemic exposure after oral administration to healthy mice and was unable to appreciably increase UGE by inhibiting renal SGLT2; in contrast, sotagliflozin administered orally to healthy mice at the same dose had excellent systemic exposure and markedly increased UGE.…”

Section: Introductionmentioning

confidence: 90%

“…,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)butanamide; LP-945013, (2S,3R,4R,5S,6R)-2-(3-(4-(3-((1-hydroxy-2-methylpropan-2-yl)amino)propoxy)benzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol; and sotagliflozin were synthesized at Lexicon Pharmaceuticals (Goodwin et al, 2008;Zambrowicz et al, 2012;Carson et al, 2014;Goodwin et al, 2017); LP-945013 has also been referred to as compound 7 (Goodwin et al, 2017). In all in vivo studies presented here, LX2761, LP-945013, and sotagliflozin were administered by oral gavage in a volume of no more than 10 ml/kg, and the vehicle was always aqueous 0.1% v/v Tween 80.…”

Section: Methodsmentioning

confidence: 99%

LX2761, a Sodium/Glucose Cotransporter 1 Inhibitor Restricted to the Intestine, Improves Glycemic Control in Mice

Powell

Smith

Doree

et al. 2017

J Pharmacol Exp Ther

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LX2761 is a potent sodium/glucose cotransporter 1 inhibitor restricted to the intestinal lumen after oral administration. Studies presented here evaluated the effect of orally administered LX2761 on glycemic control in preclinical models. In healthy mice and rats treated with LX2761, blood glucose excursions were lower and plasma total glucagon-like peptide-1 (GLP-1) levels higher after an oral glucose challenge; these decreased glucose excursions persisted even when the glucose challenge occurred 15 hours after LX2761 dosing in ad lib-fed mice. Further, treating mice with LX2761 and the dipeptidyl-peptidase 4 inhibitor sitagliptin synergistically increased active GLP-1 levels, suggesting increased LX2761-mediated release of GLP-1 into the portal circulation. LX2761 also lowered postprandial glucose, fasting glucose, and hemoglobin A1C, and increased plasma total GLP-1, during long-term treatment of mice with either early- or late-onset streptozotocin-diabetes; in the late-onset cohort, LX2761 treatment improved survival. Mice and rats treated with LX2761 occasionally had diarrhea; this dose-dependent side effect decreased in severity and frequency over time, and LX2761 doses were identified that decreased postprandial glucose excursions without causing diarrhea. Further, the frequency of LX2761-associated diarrhea was greatly decreased in mice either by gradual dose escalation or by pretreatment with resistant starch 4, which is slowly digested to glucose in the colon, a process that primes the colon for glucose metabolism by selecting for glucose-fermenting bacterial species. These data suggest that clinical trials are warranted to determine if LX2761 doses and dosing strategies exist that provide improved glycemic control combined with adequate gastrointestinal tolerability in people living with diabetes.

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Discovery of LX2761, a Sodium-Dependent Glucose Cotransporter 1 (SGLT1) Inhibitor Restricted to the Intestinal Lumen, for the Treatment of Diabetes

Cited by 54 publications

References 52 publications

What does sodium‐glucose co‐transporter 1 inhibition add: Prospects for dual inhibition

What does sodium‐glucose co‐transporter 1 inhibition add: Prospects for dual inhibition

Synthesis of Non‐Classical Arylated C‐Saccharides through Nickel/Photoredox Dual Catalysis

LX2761, a Sodium/Glucose Cotransporter 1 Inhibitor Restricted to the Intestine, Improves Glycemic Control in Mice

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