2. Academic Validation
  3. Design, synthesis and biological evaluation of novel 5-oxo-2-thioxoimidazolidine derivatives as potent androgen receptor antagonists

Design, synthesis and biological evaluation of novel 5-oxo-2-thioxoimidazolidine derivatives as potent androgen receptor antagonists

  • Eur J Med Chem. 2015 Jun 24:99:51-66. doi: 10.1016/j.ejmech.2015.05.039.
Alexandre V Ivachtchenko 1,  Yan A Ivanenkov 2,  Oleg D Mitkin 3,  Anton A Vorobiev 3,  Irina V Kuznetsova 3,  Natalia A Shevkun 3,  Angela G Koryakova 3,  Ruben N Karapetian 3,  Andrey S Trifelenkov 3,  Dmitry V Kravchenko 3,  Mark S Veselov 4,  Nina V Chufarova 5
Affiliations

Affiliations

  • 1 Alla Chem LLC, 1835 East Hallandale Beach Boulevard 442, Hallandale Beach, FL 33009, United States; Chemical Diversity Research Institute, Rabochaya Street 2a, Khimki, Moscow Region 141401, Russia; ChemDiv, 6605 Nancy Ridge Drive, San Diego, CF 92121, USA.
  • 2 Chemical Diversity Research Institute, Rabochaya Street 2a, Khimki, Moscow Region 141401, Russia; ChemDiv, 6605 Nancy Ridge Drive, San Diego, CF 92121, USA; Moscow Institute of Physics and Technology (State University), 9 Institutskiy Lane, Dolgoprudny City, Moscow Region 141700, Russia; Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory, 1/3, Moscow 119991, Russia. Electronic address: yai@chemdiv.com.
  • 3 Chemical Diversity Research Institute, Rabochaya Street 2a, Khimki, Moscow Region 141401, Russia.
  • 4 Moscow Institute of Physics and Technology (State University), 9 Institutskiy Lane, Dolgoprudny City, Moscow Region 141700, Russia; Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory, 1/3, Moscow 119991, Russia.
  • 5 Moscow Institute of Physics and Technology (State University), 9 Institutskiy Lane, Dolgoprudny City, Moscow Region 141700, Russia.
PMID: 26046313 DOI: 10.1016/j.ejmech.2015.05.039
Abstract

A series of novel highly active Androgen Receptor (AR) antagonists containing spiro-4-(5-oxo-3-phenyl-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile core was designed based on the SAR studies available from the reported AR antagonists and in silico modeling. Within the series, compound (R)-6 (ONC1-13B) and its related analogues, including its active N-dealkylated metabolite, were found to be the most potent molecules with the target activity (IC50, androgen-sensitive human PCa LNCaP cells) in the range of 59-80 nM (inhibition of PSA production). The disclosed hits were at least two times more active than bicalutamide, nilutamide and enzalutamide within the performed assay. Several compounds were classified as partial agonists. Hit-compounds demonstrated benefit pharmacokinetic profiles in rats. Comparative SAR and 3D molecular docking studies were performed for the hit compounds elucidating the observed differences in the binding potency.

Keywords

Androgen receptor; Antagonist; Antiandrogen; Prostate cancer.

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