Arylpiperazines for management of benign prostatic hyperplasia: design, synthesis, quantitative structure-activity relationships, and pharmacokinetic studies.
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.
Medicinal & Process Chemistry Division, Central Drug Research Institute (CSIR), Lucknow, India.
Amit
A
Sarswat
Rajeev
R
Kumar
Lalit
L
Kumar
Nand
N
Lal
Smriti
S
Sharma
Yenamandra S
YS
Prabhakar
Shailendra K
SK
Pandey
Jawahar
J
Lal
Vikas
V
Verma
Ashish
A
Jain
Jagdamba P
JP
Maikhuri
Diwakar
D
Dalela
Kirti
Gopal
G
Gupta
Vishnu L
VL
Sharma
D000726:Androgen Antagonists / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000096:biosynthesis; D006801:Humans; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism / Q000473:pathology; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011470:Prostatic Hyperplasia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000096:biosynthesis; D014018:Tissue Distribution
C562246:1-(4-nitro-2-(trifluoromethyl)phenyl)-4-(3-(trifluoromethyl)phenyl)piperazine; D000726:Androgen Antagonists; D000970:Antineoplastic Agents; D047629:Estrogen Receptor beta; D010879:Piperazines; D011944:Receptors, Androgen; D017430:Prostate-Specific Antigen