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.

• Authors: Yulin Wu, Christopher J Aquino, David J Cowan, Don L Anderson, Jeff L Ambroso, Michael J Bishop, Eric E Boros, Lihong Chen, Alan Cunningham, Robert L Dobbins, Paul L Feldman, Lindsey T Harston, Istvan W Kaldor, Ryan Klein, Xi Liang, Maggie S McIntyre, Christine L Merrill, Kristin M Patterson, Judith S Prescott, John S Ray, Shane G Roller, Xiaozhou Yao, Andrew Young, Josephine Yuen, Jon L Collins
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 56 Issue 12 Pg. 5094-114 (Jun 27 2013) ISSN: 1520-4804 [Electronic] United States
• PMID: 23678871 (Publication Type: Journal Article)

Chemical References

• 3-((((3R,5R)-3-butyl-3-ethyl-7-(methyloxy)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl)methyl)amino)pentanedioic acid
• Bile Acids and Salts
• Hypoglycemic Agents
• Methylamines
• Organic Anion Transporters, Sodium-Dependent
• Symporters
• Thiazepines
• sodium-bile acid cotransporter

Topics

• Animals
• Bile Acids and Salts (metabolism)
• Diabetes Mellitus, Type 2 (drug therapy)
• Dogs
• Drug Discovery
• Drug Stability
• HEK293 Cells
• Humans
• Hypoglycemic Agents (chemistry, metabolism, pharmacology, therapeutic use)
• Male
• Methylamines (chemistry, metabolism, pharmacology, therapeutic use)
• Mice
• Organic Anion Transporters, Sodium-Dependent (antagonists & inhibitors)
• Rats
• Solubility
• Symporters (antagonists & inhibitors)
• Thiazepines (chemistry, metabolism, pharmacology, therapeutic use)