Synthesis of novel benzbromarone derivatives designed to avoid metabolic activation

Bioorg Med Chem Lett. 2018 Dec 15;28(23-24):3708-3711. doi: 10.1016/j.bmcl.2018.10.023. Epub 2018 Oct 15.

Abstract

We synthesized six novel BBR derivatives that were designed to avoid metabolic activation via ipso-substitution and evaluated for their degree of toxicity and hURAT1 inhibition. It was found that all of the derivatives demonstrate lower cytotoxicity in mouse hepatocytes and lower levels of metabolic activation than BBR, while maintaining their inhibitory activity toward the uric acid transporter. We propose that these derivatives could serve as effective uricosuric agents that have much better safety profiles than BBR.

Keywords: Benzbromarone; Hepatotoxicity; Metabolic activation; URAT1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activation, Metabolic
  • Animals
  • Benzbromarone / analogs & derivatives*
  • Benzbromarone / metabolism*
  • Benzbromarone / pharmacology
  • Benzbromarone / toxicity
  • Chemistry Techniques, Synthetic
  • HEK293 Cells
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Humans
  • Mice
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Organic Anion Transporters / antagonists & inhibitors*
  • Organic Anion Transporters / metabolism
  • Organic Cation Transport Proteins / antagonists & inhibitors*
  • Organic Cation Transport Proteins / metabolism
  • Rats
  • Uric Acid / metabolism
  • Uricosuric Agents / chemistry*
  • Uricosuric Agents / metabolism*
  • Uricosuric Agents / pharmacology
  • Uricosuric Agents / toxicity

Substances

  • Organic Anion Transporters
  • Organic Cation Transport Proteins
  • SLC22A12 protein, human
  • Uricosuric Agents
  • Uric Acid
  • Benzbromarone