Arylpiperazines for Management of Benign Prostatic Hyperplasia: Design, Synthesis, Quantitative Structure鈭扐ctivity Relationships, and Pharmacokinetic Studies

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• 作者：Amit Sarswat ; Rajeev Kumar ; Lalit Kumar ; Nand Lal ; Smriti Sharma ; Yenamandra S. Prabhakar ; Shailendra K. Pandey ; Jawahar Lal ; Vikas Verma ; Ashish Jain ; Jagdamba P. Maikhuri ; Diwakar Dalela ; Kirti ; Gopal Gupta ; Vishnu L. Sharma
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：January 13, 2011
• 年：2011
• 卷：54
• 期：1
• 页码：302-311
• 全文大小：913K
• 年卷期：v.54,no.1(January 13, 2011)
• ISSN：1520-4804

文摘

A series of 27 aryl/heteroaryl/aralkyl/aroyl piperazines were synthesized, and most of these compounds reduced prostate weight of mature rats by 15鈭?7%. Three compounds, 10, 12, and 18, had better activity profile (reduced prostate weight by 47%, 43%, and 39%, respectively) than the standard drug flutamide (24% reduction). QSAR suggested structures with more cyclic and branched moieties, increased topological separation of O and N therein, and reduced solvation connectivity index for better activity. Pharmacokinetic study with compound 10 at an oral dose of 10.0 mg/kg indicated good absorption, negligible extrahepatic elimination, and rapid distribution to the target organ (prostate) but restricted entry through the blood鈭抌rain barrier. A 10-fold decrease in PSA and 15-fold increase in ER-尾 gene expressions of human prostate cancer cells (LNCaP) by compound 10 in vitro indicated AR and ER-尾 mediated actions. The findings may stimulate further explorations of identified lead for the management of benign prostatic hyperplasia.