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-β gene expressions of human prostate cancer cells (LNCaP) by compound 10 in vitro indicated AR and ER-β mediated actions. The findings may stimulate further explorations of identified lead for the management of benign prostatic hyperplasia.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Androgen Antagonists / chemical synthesis
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Androgen Antagonists / pharmacokinetics
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Androgen Antagonists / pharmacology
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Blood-Brain Barrier / metabolism
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Drug Design
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Drug Screening Assays, Antitumor
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism
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Estrogen Receptor beta / biosynthesis
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Humans
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Male
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Neoplasms, Hormone-Dependent / metabolism
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Neoplasms, Hormone-Dependent / pathology
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Piperazines / chemical synthesis*
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Piperazines / pharmacokinetics
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Piperazines / pharmacology
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Prostate / drug effects
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Prostate / metabolism
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Prostate / pathology
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Prostate-Specific Antigen / metabolism
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Prostatic Hyperplasia / drug therapy*
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Prostatic Hyperplasia / metabolism
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Prostatic Hyperplasia / pathology
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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Quantitative Structure-Activity Relationship
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Rats
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Rats, Sprague-Dawley
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Receptors, Androgen / biosynthesis
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Tissue Distribution
Substances
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1-(4-nitro-2-(trifluoromethyl)phenyl)-4-(3-(trifluoromethyl)phenyl)piperazine
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Androgen Antagonists
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Antineoplastic Agents
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Estrogen Receptor beta
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Piperazines
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Receptors, Androgen
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Prostate-Specific Antigen