Novel aryl piperazines for alleviation of ‘andropause’ associated prostatic disorders and depression

• Published in: European journal of medicinal chemistry Vol. 132; pp. 204 - 218
• Main Authors: Gupta, Sonal, Pandey, Deepti, Mandalapu, Dhanaraju, Sharma, Vikas, Shukla, Mahendra, Singh, Seema, Singh, Nidhi, Yadav, Santosh Kumar, Tanpula, Dilip Kumar, Singh, Surabhi, Maikhuri, Jagdamba P., Shukla, Shubha, Lal, Jawahar, Siddiqi, Mohammad I., Gupta, Gopal, Sharma, Vishnu L.
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 26.05.2017; Elsevier
• Subjects: Androgen Antagonists - chemical synthesis; Androgen Antagonists - pharmacology; Andropause; Animals; Cell Line; Chemistry, Medicinal; Depression - drug therapy; Down-Regulation - drug effects; Humans; Life Sciences & Biomedicine; Male; Molecular Docking Simulation; MTT assay; Pharmacokinetics; Pharmacology & Pharmacy; Piperazine derivatives; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacokinetics; Prostatic Diseases - drug therapy; Rats; Receptors, Androgen - drug effects; Science & Technology; α1A blocking activity; α1A blocking activity; DMSO; AUClast; tmax; F; MTT; MTT assay; DHT; T; OD; FBS; DMF; PSA; RFU; Cl/F; EtOAc; Cmax; SDS; TBS; FST; Et3N; Vd/F; SARM; DCM; UFLC; AR; TST; Piperazine derivatives; BPH; Pharmacokinetics; HF; 5-HT1A RECEPTORS; RATS; alpha(1A) blocking activity; HYPERPLASIA; CANCER; BENIGN; URINARY-TRACT SYMPTOMS; BIOLOGICAL EVALUATION; DERIVATIVES; ANDROGEN RECEPTOR MODULATOR; α(1A) blocking activity
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.03.036

A series of seventeen piperazine derivatives have been synthesized and biologically evaluated for the management of andropause-associated prostatic disorders and depression. Five compounds 16, 19, 20, 21 and 22 significantly inhibited proliferation of androgen-sensitive LNCaP prostatic cell line with EC50 values of 12.4 μM, 15.6 μM, 11.8 μM, 10.4 μM, 12.2 μM respectively and decreased Ca2+ entry through adrenergic-receptor α1A blocking activity. Anti-androgenic behaviour of compound 19 and 22 was evident by decreased luciferase activity. The high EC50 value in AR-negative cells PC3 and DU145 suggested that the cytotoxicity of compounds was due to AR down regulation. Compound 19 reduced the prostate weight of rats by 53.8%. Further, forced-swimming and tail-suspension tests revealed antidepressant-like activity of compound 19, lacking effects on neuromuscular co-ordination. In silico ADMET predictions revealed that the compound 19 had good oral absorption, aqueous solubility, non-hepatotoxic and good affinity for plasma protein binding. Pharmacokinetic and tissue uptake of 19 at 10 mg/kg demonstrated an oral bioavailability of 35.4%. In silico docking studies predicted similar binding pattern of compound 19 on androgen receptor as hydroxyflutamide. Compound 19 appears to be a unique scaffold with promising activities against androgen associated prostatic disorders in males like prostate cancer and BPH and associated depression. [Display omitted] •Seventeen aryl/heteroaryl piperazines designed to manage prostate and depression.•MTT assay on LNCaP cells and Ca++ mobilization in α1A expressing cells done.•Luciferase reporter gene assay and cell viability were also carried out.•In vivo, PK and docking studies of the most promising compounds accomplished.•Compound 19 may be a lead candidate for andropause associated disorders in males.