Discovery and potency optimization of 2-amino-5-arylmethyl-1,3-thiazole derivatives as potential therapeutic agents for prostate cancer.
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.
Krasavin
Mikhail
M
Department of Lead Discovery, Chemical Diversity Research Institute, Khimki, Moscow Reg., Russia. myk@chemdiv.com
Karapetian
Ruben
R
Konstantinov
Igor
I
Gezentsvey
Yuri
Y
Bukhryakov
Konstantin
K
Godovykh
Elena
E
Soldatkina
Olga
O
Lavrovsky
Yan
Y
Sosnov
Andrei V
AV
Gakh
Andrei A
AA
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D019906:Nuclear Magnetic Resonance, Biomolecular; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity
D000970:Antineoplastic Agents; D013844:Thiazoles