Discovery of a Highly Potent, Nonabsorbable Apical Sodium-Dependent Bile Acid Transporter Inhibitor (GSK2330672) for Treatment of Type 2 Diabetes

Wu, Yulin; Aquino, Christopher; Cowan, David J.; Anderson, Don L.; Ambroso, Jeffrey L.; Bishop, Michael J.; Boros, Eric E.; Chen, Lihong; Cunningham, Alan; Dobbins, Robert L.; Feldman, Paul L.; Harston, Lindsey T.; Káldor, István; Klein, Ryan R.; Liang, Xi; McIntyre, Maggie S.; Merrill, Christine L.; Patterson, Kristin M.; Prescott, Judith S.; Ray, John S.; Roller, Shane; Yao, Xing-Can; Young, Andrew; Yuen, Josephine; Collins, Jon L.

doi:10.1021/jm400459m

Cited by 72 publications

(64 citation statements)

References 21 publications

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“…Because bile acids promote the secretion of intestinal incretin peptides (such as glucagon-like peptide 1) that in turn stimulate pancreatic insulin secretion, inhibition of ASBT may also be a viable strategy for the treatment of type 2 diabetes 130 . GlaxoSmithKline recently completed two Phase II studies using a combination of GSK2330672 plus metformin to treat diabetes (NCT02202161 and NCT01929863).…”

Section: Slc Transporters As Targets Of Drugsmentioning

confidence: 99%

SLC transporters as therapeutic targets: emerging opportunities

Lin

Yee

Kim

et al. 2015

Nat Rev Drug Discov

653

552

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Solute carrier (SLC) transporters — a family of more than 300 membrane-bound proteins that facilitate the transport of a wide array of substrates across biological membranes — have important roles in physiological processes ranging from the cellular uptake of nutrients to the absorption of drugs and other xenobiotics. Several classes of marketed drugs target well-known SLC transporters, such as neurotransmitter transporters, and human genetic studies have provided powerful insight into the roles of more-recently characterized SLC transporters in both rare and common diseases, indicating a wealth of new therapeutic opportunities. This Review summarizes knowledge on the roles of SLC transporters in human disease, describes strategies to target such transporters, and highlights current and investigational drugs that modulate SLC transporters, as well as promising drug targets.

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Section: Slc Transporters As Targets Of Drugsmentioning

confidence: 99%

SLC transporters as therapeutic targets: emerging opportunities

Lin

Yee

Kim

et al. 2015

Nat Rev Drug Discov

653

552

View full text Add to dashboard Cite

show abstract

“…The main adverse events (AEs) were abdominal discomfort, nausea and mild diarrhoea, which were dose-dependent [23] . GSK2330672 has been developed as specific, non-absorbable, highly potent human ASBTi [24] and has been investigated in double-blind, randomized trials of patients with type2 diabetes mellitus [25] . It was shown to reduce circulating BAs, fasting plasma glucose and cholesterol (LDL, non-HDL and total cholesterol) levels and increase C4.…”

Section: Clinical Evidencementioning

confidence: 99%

Apical Sodium-Dependent Transporter Inhibitors in Primary Biliary Cholangitis and Primary Sclerosing Cholangitis

Hegade

Jones

Hirschfield

2017

Dig Dis

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Bile acids (BAs) have gained mainstream attention since the discovery of their key role as signalling molecules in health and disease. The apical sodium-dependent transporter (ASBT) protein located in the terminal ileum plays an important physiological role in the enterohepatic circulation of BAs and therefore essential for the BA homeostasis. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), the 2 most common cholestatic liver diseases are characterised by altered BA flow and BA composition, which contribute to disease progression and symptom (pruritus) development. Therefore, changing the circulating BA pool in patients with PBC and PSC may have therapeutic implications. To this end, pharmacological inhibition of ASBT is fast emerging as an interesting target. In this review, we discuss the recent evidence for potential therapeutic use of ASBT inhibitors to treat PBC and PSC patients.

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“…40 48 In rats, blockage of ASBT causes increased amounts of bile acids in the colon due to inhibition of the normal bile acid reabsorption by ASBT in the terminal ileum. 40 48 In rats, blockage of ASBT causes increased amounts of bile acids in the colon due to inhibition of the normal bile acid reabsorption by ASBT in the terminal ileum.…”

Section: Metforminmentioning

confidence: 99%

Evidence connecting old, new and neglected glucose‐lowering drugs to bile acid‐induced GLP‐1 secretion: A review

Kårhus

Brønden

Sonne

et al. 2017

Diabetes Obesity Metabolism

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Bile acids are amphipathic water-soluble steroid-based molecules best known for their important lipid-solubilizing role in the assimilation of fat. Recently, bile acids have emerged as metabolic integrators with glucose-lowering potential. Among a variety of gluco-metabolic effects, bile acids have been demonstrated to modulate the secretion of the gut-derived incretin hormone glucagon-like peptide-1 (GLP-1), possibly via the transmembrane receptor Takeda G-protein-coupled receptor 5 and the nuclear farnesoid X receptor, in intestinal L cells. The present article critically reviews current evidence connecting established glucose-lowering drugs to bile acid-induced GLP-1 secretion, and discusses whether bile acid-induced GLP-1 secretion may constitute a new basis for understanding how metformin, inhibitors of the apical sodium-dependent bile acids transporter, and bile acid sequestrants - old, new and neglected glucose-lowering drugs - improve glucose metabolism.

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Discovery of a Highly Potent, Nonabsorbable Apical Sodium-Dependent Bile Acid Transporter Inhibitor (GSK2330672) for Treatment of Type 2 Diabetes

Cited by 72 publications

References 21 publications

SLC transporters as therapeutic targets: emerging opportunities

SLC transporters as therapeutic targets: emerging opportunities

Apical Sodium-Dependent Transporter Inhibitors in Primary Biliary Cholangitis and Primary Sclerosing Cholangitis

Evidence connecting old, new and neglected glucose‐lowering drugs to bile acid‐induced GLP‐1 secretion: A review

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