Arylpiperazines for management of benign prostatic hyperplasia: design, synthesis, quantitative structure-activity relationships, and pharmacokinetic studies.
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Sarswat A, Kumar R, Kumar L, Lal N, Sharma S, Prabhakar YS, Pandey SK, Lal J, Verma V, Jain A, Maikhuri JP, Dalela D, Kirti, Gupta G, Sharma VL
Arylpiperazines for management of benign prostatic hyperplasia: design, synthesis, quantitative structure-activity relationships, and pharmacokinetic studies.
J Med Chem. 2011 Jan 13;54(1):302-11. doi: 10.1021/jm101163m. Epub 2010 Dec 3.
- PubMed ID
- 21128595 [ View in PubMed]
- Abstract
A series of 27 aryl/heteroaryl/aralkyl/aroyl piperazines were synthesized, and most of these compounds reduced prostate weight of mature rats by 15-47%. 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-brain barrier. A 10-fold decrease in PSA and 15-fold increase in ER-beta gene expressions of human prostate cancer cells (LNCaP) by compound 10 in vitro indicated AR and ER-beta mediated actions. The findings may stimulate further explorations of identified lead for the management of benign prostatic hyperplasia.