E297G mutated bile salt export pump (BSEP) function enhancers derived from GW4064: structural development study and separation from farnesoid X receptor-agonistic activity.

Abstract

Bile salt export pump (BSEP) is a member of the ATP-binding cassette transmembrane transporter family and mediates biliary excretion of bile acids from hepatocytes. Several BSEP mutants, including Glu297Gly (E297G) and Asp482Gly (D482G), cause progressive familial intrahepatic cholestasis type 2. We previously found that compounds based on GW4064, a representative farnesoid X receptor (FXR) agonist, enhanced E297G BSEP transport activity. Here, we conducted a structure-activity relationship analysis of GW4064 derivatives aimed at separating E297G BSEP-function-promoting activity and FXR-agonistic activity. Among newly synthesized reversed-amide derivatives of previously reported GW4064 analogs 2a-2f, we identified 7c as a selective BSEP function enhancer.

• Authors: Takashi Misawa, Hisamitsu Hayashi, Makoto Makishima, Yuichi Sugiyama, Yuichi Hashimoto
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 22 Issue 12 Pg. 3962-6 (Jun 15 2012) ISSN: 1464-3405 [Electronic] England
• PMID: 22583617 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• ATP-Binding Cassette Transporters
• Bile Acids and Salts
• Isoxazoles
• Receptors, Cytoplasmic and Nuclear
• farnesoid X-activated receptor
• GW 4064

Topics

• ATP-Binding Cassette Transporters (agonists, genetics, metabolism)
• Animals
• Bile Acids and Salts (metabolism)
• Biological Transport (drug effects)
• Cell Line
• Dogs
• Dose-Response Relationship, Drug
• Humans
• Isoxazoles (chemical synthesis, pharmacology)
• Mutation
• Receptors, Cytoplasmic and Nuclear (agonists, metabolism)
• Structure-Activity Relationship