Isocytosine-based inhibitors of xanthine oxidase: design, synthesis, SAR, PK and in vivo efficacy in rat model of hyperuricemia

Bioorg Med Chem Lett. 2012 Dec 15;22(24):7543-6. doi: 10.1016/j.bmcl.2012.10.029. Epub 2012 Oct 13.

Abstract

Structure-activity relationship studies were carried out for lead generation following structure-guided design approach from an isocytosine scaffold identified earlier for xanthine oxidase inhibition. A 470-fold improvement in in vitro IC(50) was obtained in the process. Five most potent compounds with nanomolar IC(50) values were selected for pharmacokinetics and in vivo experiments. The best compound showed good in vivo activity when administered intraperitoneally but was not active by oral route. The results suggest that improvement in oral exposure could improve the in vivo efficacy of this series.

MeSH terms

  • Administration, Oral
  • Animals
  • Cytosine / administration & dosage
  • Cytosine / analogs & derivatives*
  • Cytosine / chemical synthesis
  • Cytosine / pharmacology
  • Disease Models, Animal*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology*
  • Hyperuricemia / drug therapy*
  • Hyperuricemia / enzymology
  • Hyperuricemia / metabolism
  • Models, Molecular
  • Molecular Structure
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Structure-Activity Relationship
  • Time Factors
  • Xanthine Oxidase / antagonists & inhibitors*
  • Xanthine Oxidase / metabolism

Substances

  • Enzyme Inhibitors
  • isocytosine
  • Cytosine
  • Xanthine Oxidase