Discovery and Potency Optimization of 2-Amino-5-arylmethyl-1,3-thiazole Derivatives as Potential Therapeutic Agents for Prostate Cancer

• Published in: Archiv der Pharmazie (Weinheim) Vol. 342; no. 7; pp. 420 - 427
• Main Authors: Krasavin, Mikhail, Karapetian, Ruben, Konstantinov, Igor, Gezentsvey, Yuri, Bukhryakov, Konstantin, Godovykh, Elena, Soldatkina, Olga, Lavrovsky, Yan, Sosnov, Andrei V., Gakh, Andrei A.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.07.2009; WILEY‐VCH Verlag; Wiley
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - toxicity; Antiproliferative activity; Cell Death - drug effects; Cell Line; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Cytotoxicity; Drug Design; Drug Discovery; Drug Screening Assays, Antitumor; Drug-likeness; Humans; Life Sciences & Biomedicine; Male; Nuclear Magnetic Resonance, Biomolecular; Pharmacology & Pharmacy; Physical Sciences; Prostate cancer; Prostatic Neoplasms - drug therapy; Science & Technology; Small molecules; Structure-Activity Relationship; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology; Thiazoles - toxicity; Cytotoxicity; Small molecules; Drug-likeness; Antiproliferative activity; Prostate cancer
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.200800201

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 μM). 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.