Discovery of BI-9787, a potent zwitterionic ketohexokinase inhibitor with oral bioavailability

Bioorg Med Chem Lett. 2024 Nov 1:112:129930. doi: 10.1016/j.bmcl.2024.129930. Epub 2024 Aug 22.

Abstract

Fructose metabolism by ketohexokinase (KHK) is implicated in a variety of metabolic disorders. KHK inhibition is a potential therapeutic strategy for the treatment of diseases including diabetes, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis. The first small-molecule KHK-inhibitors have entered clinical trials, but it remains unclear if systemic inhibition of KHK by small-molecules will eventually benefit patients. Here we report the discovery of BI-9787, a potent, zwitterionic KHK inhibitor characterized by high permeability and favorable oral rat pharmacokinetics. BI-9787 was identified by optimizing chemical starting points generated via a ligand-based virtual screening of Boehringer's virtual library of synthetically accessible compounds (BICLAIM). It serves as a high-quality in vitro and in vivo tool compound for investigating the role of fructose metabolism in disease.

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability*
  • Dose-Response Relationship, Drug
  • Drug Discovery
  • Enzyme Inhibitors* / chemical synthesis
  • Enzyme Inhibitors* / chemistry
  • Enzyme Inhibitors* / pharmacokinetics
  • Enzyme Inhibitors* / pharmacology
  • Fructokinases* / antagonists & inhibitors
  • Fructokinases* / metabolism
  • Humans
  • Molecular Structure
  • Rats
  • Structure-Activity Relationship

Substances

  • ketohexokinase
  • Fructokinases
  • Enzyme Inhibitors