Design of Dimeric Bile Acid Derivatives as Potent and Selective Human NTCP Inhibitors

J Med Chem. 2021 May 13;64(9):5973-6007. doi: 10.1021/acs.jmedchem.1c00078. Epub 2021 Apr 27.

Abstract

Dimeric bile acid derivatives (DBADs) were developed and tested for their anti-HBV and anti-HDV activities as sodium taurocholate cotransporting polypeptide (NTCP) inhibitors. DBADs exhibited strong and persistent potency of NTCP inhibition, whereas diverse linkers and constitutions showed distinct inhibition features. Motif aa157-165 on NTCP was shown to be a possible binding site of DBADs; therefore, we determined DBADs' selectivity among NTCPs from different species. A cyclized DBAD scaffold DBA-41 exhibited a high affinity to human NTCP (hNTCP). Intraperitoneal administration of DBA-41 to hNTCP-tg mice induced serum total bile acid elevation. DBA-41 may serve as a biological tool to study NTCP physiological function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bile Acids and Salts / blood
  • Bile Acids and Salts / chemistry*
  • Bile Acids and Salts / pharmacology*
  • Dimerization*
  • Drug Design*
  • Humans
  • Mice
  • Organic Anion Transporters, Sodium-Dependent / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Symporters / antagonists & inhibitors*

Substances

  • Bile Acids and Salts
  • Organic Anion Transporters, Sodium-Dependent
  • Symporters
  • sodium-bile acid cotransporter