Arylpiperazines for Management of Benign Prostatic Hyperplasia: Design, Synthesis, Quantitative Structure−Activity Relationships, and Pharmacokinetic Studies
| Autor: | Gopal Gupta, Rajeev Kumar, Ashish Jain, Yenamandra S. Prabhakar, Vikas Verma, Kirti, Jagdamba P. Maikhuri, Lalit Kumar, Smriti Sharma, Diwakar Dalela, Jawahar Lal, Vishnu L. Sharma, Amit Sarswat, Pandey Shailendra Kumar, Nand Lal |
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| Rok vydání: | 2010 |
| Předmět: |
Male
medicine.medical_specialty Neoplasms Hormone-Dependent Prostatic Hyperplasia Quantitative Structure-Activity Relationship Antineoplastic Agents Pharmacology Piperazines Flutamide Rats Sprague-Dawley chemistry.chemical_compound Pharmacokinetics Prostate Internal medicine Drug Discovery LNCaP medicine Animals Estrogen Receptor beta Humans Distribution (pharmacology) Tissue Distribution Chemistry Prostatic Neoplasms Androgen Antagonists Epithelial Cells Prostate-Specific Antigen Hyperplasia medicine.disease In vitro Rats medicine.anatomical_structure Endocrinology Blood-Brain Barrier Receptors Androgen Drug Design Cancer cell Molecular Medicine Drug Screening Assays Antitumor |
| Zdroj: | Journal of Medicinal Chemistry. 54:302-311 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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