title: Design, synthesis and biological evaluation of novel 5-oxo-2-thioxoimidazolidine derivatives as potent androgen receptor antagonists.
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.
authors.affiliation: 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.
authors.forename: Alexandre V
authors.initials: AV
authors.lastname: Ivachtchenko
authors.affiliation: 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.
authors.forename: Yan A
authors.initials: YA
authors.lastname: Ivanenkov
authors.affiliation: Chemical Diversity Research Institute, Rabochaya Street 2a, Khimki, Moscow Region 141401, Russia.
authors.forename: Oleg D
authors.initials: OD
authors.lastname: Mitkin
authors.affiliation: Chemical Diversity Research Institute, Rabochaya Street 2a, Khimki, Moscow Region 141401, Russia.
authors.forename: Anton A
authors.initials: AA
authors.lastname: Vorobiev
authors.affiliation: Chemical Diversity Research Institute, Rabochaya Street 2a, Khimki, Moscow Region 141401, Russia.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Kuznetsova
authors.affiliation: Chemical Diversity Research Institute, Rabochaya Street 2a, Khimki, Moscow Region 141401, Russia.
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Shevkun
authors.affiliation: Chemical Diversity Research Institute, Rabochaya Street 2a, Khimki, Moscow Region 141401, Russia.
authors.forename: Angela G
authors.initials: AG
authors.lastname: Koryakova
authors.affiliation: Chemical Diversity Research Institute, Rabochaya Street 2a, Khimki, Moscow Region 141401, Russia.
authors.forename: Ruben N
authors.initials: RN
authors.lastname: Karapetian
authors.affiliation: Chemical Diversity Research Institute, Rabochaya Street 2a, Khimki, Moscow Region 141401, Russia.
authors.forename: Andrey S
authors.initials: AS
authors.lastname: Trifelenkov
authors.affiliation: Chemical Diversity Research Institute, Rabochaya Street 2a, Khimki, Moscow Region 141401, Russia.
authors.forename: Dmitry V
authors.initials: DV
authors.lastname: Kravchenko
authors.affiliation: 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.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Veselov
authors.affiliation: Moscow Institute of Physics and Technology (State University), 9 Institutskiy Lane, Dolgoprudny City, Moscow Region 141700, Russia.
authors.forename: Nina V
authors.initials: NV
authors.lastname: Chufarova
mesh_terms: D059002:Androgen Receptor Antagonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D006801:Humans; D048289:Imidazolidines / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000737:chemistry / Q000378:metabolism*
chemical_list: D059002:Androgen Receptor Antagonists; D048289:Imidazolidines; D011944:Receptors, Androgen
keywords: Androgen receptor; Antagonist; Antiandrogen; Prostate cancer