Discovery of 3-aryloxy-lactam analogs as potent androgen receptor full antagonists for treating castration resistant prostate cancer

Bioorg Med Chem Lett. 2012 Jan 15;22(2):1230-6. doi: 10.1016/j.bmcl.2011.11.068. Epub 2011 Dec 9.

Abstract

High throughput cell-based screening led to the identification of 3-aryloxy lactams as potent androgen receptor (AR) antagonists. Refinement of these leads to improve the ADME profile and remove residual agonism led to the discovery of 12, a potent full antagonist with greater oral bioavailability. Improvements in the ADME profile were realized by designing more ligand-efficient molecules with reduced molecular weights and lower lipophilicities.

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • High-Throughput Screening Assays
  • Humans
  • Lactams / chemical synthesis
  • Lactams / chemistry
  • Lactams / pharmacology*
  • Male
  • Models, Molecular
  • Molecular Structure
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / surgery
  • Receptors, Androgen / chemistry*
  • Receptors, Androgen / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Lactams
  • Receptors, Androgen