90357-51-0Relevant articles and documents
Novel trifluoromethylated enobosarm analogues with potent antiandrogenic activity in vitro and tissue selectivity in vivo
Alwyn Dart,Kandil, Sahar,Tommasini-Ghelfi, Serena,Serrano de Almeida, Gilberto,Bevan, Charlotte L.,Jiang, Wenguo,Westwell, Andrew D.
, p. 1846 - 1858 (2018)
Prostate cancer often develops antiandrogen resistance, possibly via androgen receptor (AR) mutations, which change antagonists to agonists. Novel therapies with increased anticancer activity, while overcoming current drug resistance are urgently needed. Enobosarm has anabolic effects on muscle and bone while having no effect on the prostate. Here, we describe the activity of novel chemically modified enobosarm analogues. The rational addition of bistrifluoromethyl groups into ring B of enobosarm, profoundly modified their activity, pharmacokinetic and tissue distribution profiles. These chemical structural modifications resulted in an improved AR binding affinity—by increasing the molecular occupational volume near helix 12 of AR. In vitro, the analogues SK33 and SK51 showed very potent antiandrogenic activity, monitored using LNCaP/ ARLuciferase cells where growth, PSA and luciferase activity were used as AR activity measurements. These compounds were 10-fold more potent than bicalutamide and 100-fold more potent than enobosarm within the LNCaP model. These compounds were also active in LNCaP/BicR cells with acquired bicalutamide resistance. In vivo, using the ARLuc reporter mice, these drugs showed potent AR inhibitory activity in the prostate and other ARexpressing tissues, e.g., testes, seminal vesicles, and brain. These compounds do not inhibit AR activity in the skeletal muscle, and spleen, thus indicating a selective tissue inhibitory profile. These compounds were also active in vivo in the Pb-Pten deletion model. SK33 and SK51 have significantly different and enhanced activity profiles compared with enobosarm and are ideal candidates for further development for prostate cancer therapy with potentially fewer side effects.
Preparation method of bicalutamide
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Paragraph 0033-0042, (2021/01/11)
The invention provides a preparation method of bicalutamide. The method comprises the following steps: dissolving N-[4-cyano-3-(trifluoromethyl) phenyl]-2-methacrylamide in a lower fatty acid ester solvent, sequentially adding sodium percarbonate and acetic anhydride, performing stirring and heating, and carrying out epoxidation reaction to obtain a reaction solution; filtering the reaction solution, washing the organic phase with a sodium thiosulfate solution, and recovering the solvent under reduced pressure; and adding petroleum ether, performing cooling, crystallizing, filtering, and drying to obtain bicalutamide. The preparation method of bicalutamide provided by the invention has the advantages of mild reaction conditions, high reaction yield, high epoxidation efficiency and recyclable reaction solvent.
A new series of bicalutamide, enzalutamide and enobosarm derivatives carrying pentafluorosulfanyl (SF5) and pentafluoroethyl (C2F5) substituents: Improved antiproliferative agents against prostate cancer
Pertusati, Fabrizio,Ferla, Salvatore,Bassetto, Marcella,Brancale, Andrea,Khandil,Westwell, Andrew D.,McGuigan, Christopher
, p. 1 - 14 (2019/07/10)
SAR studies on bicalutamide, enobosarm and enzalutamide analogues, functionalised with polyfluorinated groups, is presented. Among the novel bicalutamide and enobosarm derivatives synthesised, several displayed significantly improved in vitro anticancer activity, with IC50 values in the low micromolar range against four different prostate cancer cell lines (LNCaP, VCaP, DU-145 and 22Rv1), showing up to 48-fold increase in comparison with the parent structures. In particular, SF5 enobosarm analogues were found to be most potent compounds, full AR antagonists and with favourable ADME properties. The most promising compound (48a) was evaluated for its in vivo efficacy in PC xenograft mouse model (22Rv1) with results comparable to the standard-of-care docetaxel.
