Tandem optimization of target activity and elimination of mutagenic potential in a potent series of N-aryl bicyclic hydantoin-based selective androgen receptor modulators

Bioorg Med Chem Lett. 2007 Apr 1;17(7):1860-4. doi: 10.1016/j.bmcl.2007.01.076. Epub 2007 Jan 27.


Pharmacokinetic studies in cynomolgus monkeys with a novel prototype selective androgen receptor modulator revealed trace amounts of an aniline fragment released through hydrolytic metabolism. This aniline fragment was determined to be mutagenic in an Ames assay. Subsequent concurrent optimization for target activity and avoidance of mutagenicity led to the identification of a pharmacologically superior clinical candidate without mutagenic potential.

MeSH terms

  • Androgen Antagonists / chemical synthesis*
  • Androgen Antagonists / chemistry*
  • Androgen Antagonists / pharmacology
  • Animals
  • Chemistry, Pharmaceutical / methods*
  • Drug Design
  • Escherichia coli / metabolism
  • Genes, Reporter
  • Hydantoins / chemical synthesis*
  • Hydantoins / chemistry*
  • Kinetics
  • Macaca fascicularis
  • Models, Chemical
  • Molecular Conformation
  • Mutagenesis
  • Mutagens
  • Receptors, Androgen / metabolism*
  • Structure-Activity Relationship


  • Androgen Antagonists
  • Hydantoins
  • Mutagens
  • Receptors, Androgen