Discovery and biological characterization of a novel series of androgen receptor modulators

Abstract

Background and purpose: Selective androgen receptor modulators are of great value in the treatment of prostate cancer. The purpose of this study was to provide a preliminary characterization of a new class of non-steroidal androgen receptor modulators discovered in a high-throughput screening campaign. Experimental approach: Competitive receptor binding, luciferase-based reporter methods, cell proliferation and in vivo assays were employed to evaluate an initial set of compounds from chemistry efforts. Key results: Forty-nine analogues from the chemistry efforts showed high affinity binding to androgen receptors, agonist and/ or antagonist activities in both CV-1 and MDA-MB-453 transfection assays. A proliferation assay in LNCaP cells also exhibited this profile. A representative of these non-steroidal compounds (compound 21) was devoid of activity at other nuclear receptors (oestrogen, progesterone, glucocorticoid and mineralocorticoid receptors) in the CV-1 co-transfection assay. At the same time, in an immature castrated rat model, it behaved as an androgen receptor antagonist against the growth of prostate, seminal vesicles and levator ani induced by exogenous androgen. Separation of compound 21 into its enantiomers showed that nearly all the androgen receptor modulating activity and binding resided in the dextrorotatory compound (23) while the laevorotatory isomer (22) possessed weak or little effect depending on the cell type studied. Conclusions and implications: These non-steroidal compounds may represent a new class of androgen receptor modulators for the treatment of not only prostate cancer but other clinical conditions where androgens and androgen receptors are involved in the pathological processes.

Mannich bases in medicinal chemistry and drug design

“…Subsequent activation of androgen-responsive genes can be blocked by androgen receptor antagonists through competitive inhibition. Highthroughput screening of a structurally diverse chemical library comprising 16,000 synthetic and natural compounds led to the identification of 130 hit compounds that exhibited more than 85% competitive inhibition of 5a-dihydrotestosterone binding to androgen receptor [506]. Mannich base 360 (R 1 ¼ R 2 ¼ CH 3 , R 3 ¼ C 6 H 5 ) ( Fig.…”

Identification of Mannich Base as a Novel Inhibitor of Mycobacterium Tuberculosis Isocitrate by High-Throughput Screening

“…more diverse activities were reported, such as: anti-androgen20, insulin sensitizer, excited peroxisome proliferator-activated receptors (PPARs), inhibit cholesterol acyltransferase (ACAT), and promote high-density lipoprotein receptor (SRBI) expression and reverse tumor multi-drug resistance, such as pharmacological activity, can be used as the prevention and treatment of insulin resistance-related diseases, diabetes, obesity, atherosclerosis, fatty liver, hyperlipidemia, inflammation, tumor diseases, such as multi-drug resistance of the drug/precursor material 21-24. Our working hypothesis is these compounds might be active against ICL.…”

Synthesis and Evaluation of 5-(6-Methoxynaphthalen-2-Yl)-1-Aryl-1-(4-(Trifluoromethyl)phenylamino)pentan-3-One as Potential Antidiabetic Agents

“…Notably, it is a classical method for the preparation of β-amino ketones. Efforts have been devoted to the pharmaceutical activities of β-amino ketones for anticancer 11 , antibacterial 12 , anti-inflammatory 13 and antiandrogen 14 , but little study has been directed to investigate the antidiabetic activity of β-amino ketones.…”