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

Abstract

The apical sodium-dependent bile acid transporter (ASBT) transports bile salts from the lumen of the gastrointestinal (GI) tract to the liver via the portal vein. Multiple pharmaceutical companies have exploited the physiological link between ASBT and hepatic cholesterol metabolism, which led to the clinical investigation of ASBT inhibitors as lipid-lowering agents. While modest lipid effects were demonstrated, the potential utility of ASBT inhibitors for treatment of type 2 diabetes has been relatively unexplored. We initiated a lead optimization effort that focused on the identification of a potent, nonabsorbable ASBT inhibitor starting from the first-generation inhibitor 264W94 (1). Extensive SAR studies culminated in the discovery of GSK2330672 (56) as a highly potent, nonabsorbable ASBT inhibitor which lowers glucose in an animal model of type 2 diabetes and shows excellent developability properties for evaluating the potential therapeutic utility of a nonabsorbable ASBT inhibitor for treatment of patients with type 2 diabetes.

SLC transporters as therapeutic targets: emerging opportunities

“…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).…”

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

“…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.…”

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

“…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.…”