90357-51-0Relevant academic research and scientific papers
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.
Synthesis, biological evaluation and X-ray analysis of bicalutamide sulfoxide analogues for the potential treatment of prostate cancer
Kandil, Sahar B.,Kariuki, Benson M.,McGuigan, Christopher,Westwell, Andrew D.
, (2021/02/16)
The androgen receptor (AR) is a pivotal target for the treatment of prostate cancer (PC) even when the disease progresses toward androgen-independent or castration-resistant forms. In this study, a series of sulfoxide derivatives were prepared and their antiproliferative activity evaluated in vitro against four different human prostate cancer cell lines (22Rv1, DU-145, LNCaP and VCap). Bicalutamide and enzalutamide were used as positive controls. Compound 28 displayed significant enhancement in anticancer activity across the four PC cell lines with IC50 = 9.09 – 31.11 μM compared to the positive controls: bicalutamide (IC50 = 45.20 –51.61 μM) and enzalutamide (IC50 = 11.47 – 53.04 μM). Sulfoxide derivatives of bicalutamide were prepared efficiently from the corresponding sulfides using only one equivalent of mCPBA, limiting the reaction time to 15–30 min and maintaining the temperature at 0 °C. Interestingly, three pairs of sulfoxide diastereomers were separated and NMR comparison of their diastereotopic methylene (CH2) group is presented. X-ray diffraction crystal structure analysis provided relative configuration assignment at the chiral sulfur and carbon centres. Molecular modelling study of the four diastereoisomers of compound 28 is described.
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.
Synthetic method N-(4-cyano -3-(trifluoromethyl) phenyl)-2- methyl epoxy acrylate -2- amide (by machine translation)
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Paragraph 0041-0046, (2020/05/29)
The synthesis method N - (4 of) cyano - 3 3 3-(trifluoromethyl) - 2 - phenyl, methyl epoxy acrylate - 2 2-amide :S1,) comprises the following processing steps 4 - dissolving, amino - 2 2-trifluoromethyl-phenyl, methacrylamide 10-65 °C, into a solvent 1-10h;S2, and heating to, filtering and drying to obtain N - (4 - cyano - 3 3-trifluoromethyl-phenyl)-methacrylamide. The present invention provides ;S3,cyano - 3 3 (trifluoromethyl N - (4 - phenyl)-methyl-epoxypropane - 2 2-amide) is obtained by filtration and drying, below, ° C. The reaction 1-3h;S4, is stirred 10-24h, and dried to obtain a mixture solution of the two-phase, catalyst and manganese dioxide 20-25 °C, by filtration and drying at a temperature of about N - (4 °C. after the reaction) of the reaction mixture, is dried by filtration and drying in a mixed, solution at a, temperature in a range of) - 2 - ° C. or lower; ° C. or less. (by machine translation)
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.
Preparation method of bicalutamide epoxy intermediate
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Paragraph 0016; 0018-0022, (2019/03/28)
The invention relates to synthesis of chemical drugs, and relates to a preparation method of a bicalutamide epoxy intermediate, in particular to a preparation method of N-[4-cyano-3-(trifluoromethyl)phenyl]-1,2-epoxy-2-methylpropionamide. According to the method, lower fatty acid ester serves as a solvent, 4-cyano-3-(trifluoromethyl)aniline as a raw material is subjected to two-step reaction of methyl propene acylation and epoxidation to generate N-[4-cyano-3-(trifluoromethyl)phenyl]-2,3-epoxy-2-methylpropionamide, an acid-binding agent is used as a catalyst in methyl propene acylation reaction, and hydrogen peroxide serves as a peroxide source in epoxidation reaction. According to the method, the preparation and reaction conditions are mild, the use of trichloroethane and diethyl ether with extremely high danger is avoided, the intermediate product can be directly applied to the epoxidation reaction without separation and refining, the operation is convenient, and the working time isrelatively short.
SELECTIVE ANDROGEN RECEPTOR DEGRADER (SARD) LIGANDS AND METHODS OF USE THEREOF
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Paragraph 00471-00474, (2019/12/04)
This invention is directed to selective androgen receptor degrader (SARD) compounds including heterocyclic rings and pharmaceutical compositions and uses thereof in treating prostate cancer, advanced prostate cancer, castration resistant prostate cancer, triple negative breast cancer, other cancers expressing the androgen receptor, androgenic alopecia or other hyperandrogenic dermal diseases, Kennedys disease, amyotrophic lateral sclerosis (ALS), abdominal aortic aneurysm (AAA), and uterine fibroids, and to methods for reducing the levels of androgen receptor-full length (AR-FL) including pathogenic or resistance mutations, AR-splice variants (AR-SV), and pathogenic polyglutamine (polyQ) polymorphisms of AR in a subject.
METHODS OF TREATING ADVANCED PROSTATE CANCER
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Paragraph 0015; 0126, (2018/11/21)
Provided herein are methods for treating metastatic prostate cancer using anti-androgen compounds and radionuclide-labeled androgens.
N-[4-cyanogroup-3-(trifluoromethyl) phenyl]-2, 3-epoxy-2-methyl propanamide preparation method
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Paragraph 0015, (2017/07/21)
The invention relates to an N-[4-cyanogroup-3-(trifluoromethyl) phenyl]-2, 3-epoxy-2-methyl propanamide preparation method which is characterized in that N-[4-cyanogroup-3-(trifluoromethyl) phenyl]-2-methyl-2-acrylamide and phthalic anhydride are added into a solvent, hydrogen peroxide is added drop by drop, thermal reaction is performed at the temperature of 20-90 DEG C after adding, the content of raw materials such as the N-[4-cyanogroup-3-(trifluoromethyl) phenyl]-2-methyl-2-acrylamide in HPLC (high performance liquid chromatography) is controlled to be lower than 0.5%, reaction is finished and then the solvent is distilled off in a decompressed manner to obtain a crude product, the crude product is added into water with the weight accounting for 5-10 times that of the phthalic anhydride, alkali and sodium sulfite are added and sufficiently mixed with the water for 0.3-1.5 hours, and the product is filtered, washed and dried to obtain finished N-[4-cyanogroup-3-(trifluoromethyl) phenyl]-2, 3-epoxy-2-methyl propanamide. The preparation method has the advantages of production safety and reliability and low production cost.
Design and synthesis of novel bicalutamide and enzalutamide derivatives as antiproliferative agents for the treatment of prostate cancer
Bassetto, Marcella,Ferla, Salvatore,Pertusati, Fabrizio,Kandil, Sahar,Westwell, Andrew D.,Brancale, Andrea,McGuigan, Christopher
, p. 230 - 243 (2016/05/10)
Prostate cancer (PC) is one of the major causes of male death worldwide and the development of new and more potent anti-PC compounds is a constant requirement. Among the current treatments, (R)-bicalutamide and enzalutamide are non-steroidal androgen receptor antagonist drugs approved also in the case of castration-resistant forms. Both these drugs present a moderate antiproliferative activity and their use is limited due to the development of resistant mutants of their biological target. Insertion of fluorinated and perfluorinated groups in biologically active compounds is a current trend in medicinal chemistry, applied to improve their efficacy and stability profiles. As a means to obtain such effects, different modifications with perfluoro groups were rationally designed on the bicalutamide and enzalutamide structures, leading to the synthesis of a series of new antiproliferative compounds. Several new analogues displayed improved in vitro activity towards four different prostate cancer cell lines, while maintaining full AR antagonism and therefore representing promising leads for further development. Furthermore, a series of molecular modelling studies were performed on the AR antagonist conformation, providing useful insights on potential protein-ligand interactions.
