Systematic structure modifications of imidazo[1,2-a]pyrimidine to reduce metabolism mediated by aldehyde oxidase (AO)

J Med Chem. 2011 Nov 10;54(21):7705-12. doi: 10.1021/jm2010942. Epub 2011 Oct 10.

Abstract

N-{trans-3-[(5-Cyano-6-methylpyridin-2-yl)oxy]-2,2,4,4-tetramethylcyclobutyl}imidazo[1,2-a]pyrimidine-3-carboxamide (1) was recently identified as a full antagonist of the androgen receptor, demonstrating excellent in vivo tumor growth inhibition in castration-resistant prostate cancer (CRPC). However, the imidazo[1,2-a]pyrimidine moiety is rapidly metabolized by aldehyde oxidase (AO). The present paper describes a number of medicinal chemistry strategies taken to avoid the AO-mediated oxidation of this particular system. Guided by an AO protein structure-based model, our investigation revealed the most probable site of AO oxidation and the observation that altering the heterocycle or blocking the reactive site are two of the more effective strategies for reducing AO metabolism. These strategies may be useful for other drug discovery programs.

MeSH terms

  • Aldehyde Oxidase / chemistry*
  • Aldehyde Oxidase / metabolism
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry*
  • Catalytic Domain
  • Cyclobutanes / chemistry*
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry*
  • Imidazoles / metabolism
  • Models, Molecular
  • Oxidation-Reduction
  • Protein Binding
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Bridged Bicyclo Compounds, Heterocyclic
  • Cyclobutanes
  • Imidazoles
  • N-(3-((5-cyano-6-methylpyridin-2-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)imidazo(1,2-a)pyrimidine-3-carboxamide
  • Pyrimidines
  • Aldehyde Oxidase