Discovery and potency optimization of 2-amino-5-arylmethyl-1,3-thiazole derivatives as potential therapeutic agents for prostate cancer

Arch Pharm (Weinheim). 2009 Jul;342(7):420-7. doi: 10.1002/ardp.200800201.

Abstract

A new chemical series was identified via high-throughput screening as having antiproliferative activity on DU-145 human prostate carcinoma cell line (hit compound potency - 2.9 microM). Medicinal chemistry optimization of two peripheral diversity vectors of the hit molecule, independently, led to SAR generalizations and identification of the 'best' moieties. The latter were merged in a single compound that exhibited an over 100-fold better potency than the hit compound. For the most potent compounds it was confirmed that the observed antiproliferative potency was not associated with the compounds' non-specific cytotoxicity.

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / toxicity
  • Cell Death / drug effects
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Design
  • Drug Discovery
  • Drug Screening Assays, Antitumor
  • Humans
  • Male
  • Nuclear Magnetic Resonance, Biomolecular
  • Prostatic Neoplasms / drug therapy*
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis*
  • Thiazoles / chemistry
  • Thiazoles / pharmacology*
  • Thiazoles / toxicity

Substances

  • Antineoplastic Agents
  • Thiazoles