- Novel trifluoromethylated enobosarm analogues with potent antiandrogenic activity in vitro and tissue selectivity in vivo
-
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.
- Alwyn Dart,Kandil, Sahar,Tommasini-Ghelfi, Serena,Serrano de Almeida, Gilberto,Bevan, Charlotte L.,Jiang, Wenguo,Westwell, Andrew D.
-
-
Read Online
- Preparation method of bicalutamide
-
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.
- -
-
Paragraph 0033-0042
(2021/01/11)
-
- Synthesis, biological evaluation and X-ray analysis of bicalutamide sulfoxide analogues for the potential treatment of prostate cancer
-
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.
- Kandil, Sahar B.,Kariuki, Benson M.,McGuigan, Christopher,Westwell, Andrew D.
-
supporting information
(2021/02/16)
-
- Synthetic method N-(4-cyano -3-(trifluoromethyl) phenyl)-2- methyl epoxy acrylate -2- amide (by machine translation)
-
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)
- -
-
Paragraph 0041-0046
(2020/05/29)
-
- A new series of bicalutamide, enzalutamide and enobosarm derivatives carrying pentafluorosulfanyl (SF5) and pentafluoroethyl (C2F5) substituents: Improved antiproliferative agents against prostate cancer
-
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.
- Pertusati, Fabrizio,Ferla, Salvatore,Bassetto, Marcella,Brancale, Andrea,Khandil,Westwell, Andrew D.,McGuigan, Christopher
-
supporting information
p. 1 - 14
(2019/07/10)
-
- Preparation method of bicalutamide epoxy intermediate
-
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.
- -
-
Paragraph 0016; 0018-0022
(2019/03/28)
-
- SELECTIVE ANDROGEN RECEPTOR DEGRADER (SARD) LIGANDS AND METHODS OF USE THEREOF
-
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.
- -
-
Paragraph 00471-00474
(2019/12/04)
-
- METHODS OF TREATING ADVANCED PROSTATE CANCER
-
Provided herein are methods for treating metastatic prostate cancer using anti-androgen compounds and radionuclide-labeled androgens.
- -
-
Paragraph 0015; 0126
(2018/11/21)
-
- N-[4-cyanogroup-3-(trifluoromethyl) phenyl]-2, 3-epoxy-2-methyl propanamide preparation method
-
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.
- -
-
Paragraph 0015
(2017/07/21)
-
- Design and synthesis of novel bicalutamide and enzalutamide derivatives as antiproliferative agents for the treatment of prostate cancer
-
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.
- Bassetto, Marcella,Ferla, Salvatore,Pertusati, Fabrizio,Kandil, Sahar,Westwell, Andrew D.,Brancale, Andrea,McGuigan, Christopher
-
supporting information
p. 230 - 243
(2016/05/10)
-
- Rational design and synthesis of novel anti-prostate cancer agents bearing a 3,5-bis-trifluoromethylphenyl moiety
-
Prostate cancer is a major cause of male death worldwide and the identification of new and improved treatments is constantly required. Among the available options, different non-steroidal androgen receptor (AR) antagonists are approved also to treat castration-resistant forms. Most of these drugs show limited application due to the development of resistant mutants of their biological target. Following docking-based studies on a homology model for the AR open antagonist conformation, a series of novel 3,5-bis-trifluoromethylphenyl compounds was designed with the aim to improve the antiproliferative activity of anti-androgen drugs bicalutamide and enzalutamide. The new structural modifications might impede the receptor to adopt its closed agonist conformation also in the presence of adaptive mutations. Among the novel compounds synthesised, several displayed significantly improved in vitro activity in comparison with the parent structures, with IC50values in the low micromolar range against four different prostate cancer cell lines (LNCaP, VCaP, DU-145, 22Rv1). Selected hits demonstrated full AR antagonistic behaviour and promising candidates for further development were identified.
- Ferla, Salvatore,Bassetto, Marcella,Pertusati, Fabrizio,Kandil, Sahar,Westwell, Andrew D.,Brancale, Andrea,McGuigan, Christopher
-
supporting information
p. 3636 - 3640
(2016/07/21)
-
- Novel pathway for the synthesis of arylpropionamide-derived selective androgen receptor modulator (SARM) metabolites of andarine and ostarine
-
O-Dephenylandarine and O-dephenylostarine, two SARM metabolites relevant for doping control analysis, were synthesized in their endogenous (S)-forms as well as in terms of their racemates. The enantiopure (S)-metabolites were obtained after six steps in 20% and 23% overall yield, the slightly modified racemic route provided the compounds in 28% and 31% total yield, respectively.
- Schragl, Katharina M.,Forsdahl, Guro,Gmeiner, Guenter,Enev, Valentin S.,Gaertner, Peter
-
supporting information
p. 2239 - 2242
(2013/05/09)
-
- Antitumor agents 290. Design, synthesis, and biological evaluation of new LNCaP and PC-3 cytotoxic curcumin analogs conjugated with anti-androgens
-
In our continuing study of curcumin analogs as potential anti-prostate cancer drug candidates, 15 new curcumin analogs were designed, synthesized and evaluated for cytotoxicity against two human prostate cancer cell lines, androgen-dependent LNCaP and androgen-independent PC-3. Twelve analogs (5-12, 15, 16, 19, and 20) are conjugates of curcumin (1) or methyl curcumin (2) with a flutamide- or bicalutamide-like moiety. Two compounds (22 and 23) are C4-mono- and difluoro-substituted analogs of dimethyl curcumin (DMC, 21). Among the newly synthesized conjugates compound 15, a conjugate of 2 with a partial bicalutamide moiety, was more potent than bicalutamide alone and essentially equipotent with 1 and 2 against both prostate tumor cell lines with IC 50 values of 41.8 μM (for LNCaP) and 39.1 μM (for PC-3). A cell morphology study revealed that the cytotoxicity of curcumin analogs or curcumin-anti-androgen conjugates detected from both prostate cancer cell lines might be due to the suppression of pseudopodia formation. A molecular intrinsic fluorescence experiment showed that 1 accumulated mainly in the nuclei, while conjugate 6 was distributed in the cytosol. At the tested conditions, anti-androgens suppressed pseudopodia formation in PC-3 cells, but not in LNCaP cells. The evidence suggests that distinguishable target proteins are involved, resulting in the different outcomes toward pseudopodia suppression.
- Shi, Qian,Wada, Koji,Ohkoshi, Emika,Lin, Li,Huang, Rong,Morris-Natschke, Susan L.,Goto, Masuo,Lee, Kuo-Hsiung
-
experimental part
p. 4020 - 4031
(2012/09/08)
-
- Unexpected binding orientation of bulky-B-ring anti-androgens and implications for future drug targets
-
Several new androgen receptor antagonists were synthesized and found to have varying activities across typically antiandrogen resistant mutants (Thr877 → Ala and Trp741 → Leu) and markedly improved potency over previously reported panantagonists. X-ray crystallography of a new anti-androgen in an androgen receptor mutant (Thr877 → Ala) shows that the receptor can accommodate the added bulk presented by phenyl to naphthyl substitution, casting doubt on previous reports of predicted binding orientation and the causes of antagonism in bulky-B-ring antagonists.
- Duke III, Charles B.,Jones, Amanda,Bohl, Casey E.,Dalton, James T.,Miller, Duane D.
-
supporting information; experimental part
p. 3973 - 3976
(2011/08/05)
-
- Synthesis and biological activity of ferrocenyl derivatives of the non-steroidal antiandrogens flutamide and bicalutamide
-
A series of ferrocenyl derivatives of the two non steroidal antiandrogens flutamide and bicalutamide have been prepared. Ferrocenyl bicalutamide complexes were initially synthesized in their racemic forms, and subsequently prepared as pure (R) and (S) enantiomers, and their structure was determined by X-ray crystallography. Most of the complexes retain a modest affinity for the androgen receptor and show an antiproliferative effect on both hormone-dependent (LNCaP) and -independent (PC-3) prostate cancer cells. Ferrocenyl derivatives of bicalutamide are the most cytotoxic (IC50 values on PC-3 around 15 μM); however, they are less potent than the ferrocenyl derivatives of ethynyltestosterone or nilutamide (IC50 around 5 μM).
- Payen, Olivier,Top, Siden,Vessires, Anne,Brulé, Emilie,Lauzier, Agns,Plamont, Marie-Aude,McGlinchey, Michael J.,Müller-Bunz, Helge,Jaouen, Gérard
-
experimental part
p. 1049 - 1056
(2011/04/22)
-
- Mechanistic studies on the synthesis of bicalutamide
-
Bicalutamide, a therapeutically important anti-androgen used in the treatment of hormone-sensitive cancers, may be synthesised from the appropriate halohydrin or epoxide. We report here studies aimed at demonstrating unambiguously that preparation of bica
- Asaad, Nabil,Fillery, Shaun
-
supporting information; experimental part
p. 678 - 686
(2009/06/19)
-
- Synthesis and biological evaluation of [18F]bicalutamide, 4-[76Br]bromobicalutamide, and 4-[76Br]bromo- thiobicalutamide as non-steroidal androgens for prostate cancer imaging
-
Androgen receptors (AR) are overexpressed in most primary and metastatic prostate cancers. To develop a nonsteroidal AR-mediated imaging agent, we synthesized and radiolabeled several analogs of the potent antiandrogen bicalutamide: [18F]bicalutamide, 4-[76Br] bromobicalutamide, and [76Br]bromo-thiobicalutamide. Two of these analogs, 4-[76Br]bromobicalutamide and [76Br]bromo- thiobicalutamide, were found to have a substantially increased affinity for the androgen receptor (AR) compared to that of bicalutamide. The synthesis of [ 18F]bicalutamide utilized a pseudocarrier approach to effect addition of a carbanion generated from tracer-level amounts of a radiolabeled precursor to an unlabeled carbonyl precursor. 4-[76Br]Bromobicalutamide and [76Br]bromo-thiobicalutamide were labeled through electrophilic bromination of a tributylstannane precursor. The former could be prepared in high specific activity, and its tissue distribution was tested in vivo. Androgen target tissue uptake was evident in castrated adult male rats; however, in DES-treated, AR-positive, tumor-bearing male mice, tumor uptake was low.
- Parent, Ephraim E.,Dence, Carmen S.,Jenks, Carl,Sharp, Terry L.,Welch, Michael J.,Katzenellenbogen, John A.
-
p. 1028 - 1040
(2008/02/01)
-
- PROCESS FOR PRODUCING BICALUTAMIDE AND METHOD OF PURIFYING INTERMEDIATE THEREFOR
-
The present invention provides a process for producing bicartamide of the formula (4); which comprises Step A comprising reacting Compound (1) of the formula (1); with peroxycarboxylic acid to obtain Compound (2) of the formula (2); Step B comprising reacting said Compound (2) with 4-fluorothiophenol to obtain crude crystals of Compound (3) of the formula (3); dissolving the crude crystals in a solvent and crystallizing to obtain purified crystals of Compound (3), andStep C comprising reacting Compound (3) and percarboxylic acid to obtain bicalutamide, and also provides a method for purifying crystals of Compound (3) which comprises dissolving crude crystals of Compound (3) in a solvent and crystallizing.
- -
-
Page/Page column 11; 12-13
(2008/06/13)
-
- NOVEL HETEROCYCLE DERIVATIVES USEFUL AS SELECTIVE ANDROGEN RECEPTOR MODULATORS (SARMS)
-
The present invention is directed to novel heterocycle derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by the androgen receptor.
- -
-
Page/Page column 144-145
(2008/06/13)
-
- A PROCESS FOR THE PRODUCTION OF N-(4-CYANO-3-TRIFLUOROMETHYLPHENYL)-2,3-EPOXY-2-METHYLPROPANAMIDE
-
A process for the production of N-(4-cyano-3-trifluoromethylphenyl)-2,3-epoxy-2-methylpropanamide is characterized in that N-(4-cyano-3-trifluoromethylphenyl)-2-ethylpropenamide is epoxidized using a mixture of the urea-hydrogen peroxide complex (UHP) with either a cyclic dicarboxylic acid anhydride of formula 3, where groups R1 and R2 are the same or different and are a hydrogen atom, a C1-4-alkyl group, an aryl group or a halogen atom, or with a cyclic dicarboxylic acid anhydride of formula 4, where X is a hydrogen atom, a C1-4-alkyl group, a halogen atom, a nitro group, a cyano group or a trifluoromethyl group. N- (4-cyano-3-trifluoromethylphenyl)-2,3-epoxy-2-ethylpropanamide is an intermediate in the production of an antiandrogenic substance.
- -
-
-
- Process for making bicalutamide and intermediates thereof
-
Bicalutamide and/or its intermediates are made by the use of p-fluorobenzenesulfinic acid salt as a reagent.
- -
-
-
- Nucleophilic Aromatic Substitution of Methacrylamide Anion and Its Application to the Synthesis of the Anticancer Drug Bicalutamide
-
The anticancer drug (R,S)-biscaltamide was prepared in three steps in >90% overall yield. A key step in the new synthesis involved a new nucleophilic aromatic substitution reaction of methacrylamide anion.
- Chen, Bang-Chi,Zhao, Rulin,Gove, Stacey,Wang, Bei,Sundeen, Joseph E.,Salvati, Mark E.,Barrish, Joel C.
-
p. 10181 - 10182
(2007/10/03)
-
- Crystal of bicalutamide and production method thereof
-
The present invention relates to a crystal of bicalutamide having a defined form, as well as economical and industrially practical production methods of bicalutamide and a crystal thereof, which are superior in environmental benignity and safety. Accordingly, the present invention provides a production method of bicalutamide represented by the formula (I): which includes at least a step of reacting a compound represented by the formula (3): with an oxidizing agent, a production method of a crystal of bicalutamide, as well as a crystal form of bicalutamide as defined by X-ray diffraction (XRD) or solid 13C NMR measurement.
- -
-
Page/Page column 5; 11
(2008/06/13)
-
- Process for making bicalutamide and intermediates thereof
-
Bicalutamide and/or its intermediates are made by the use of p-fluorobenzenesulfinic acid salt as a reagent.
- -
-
-
- Nonsteroidal antiandrogens. Synthesis and structure-activity relationship of 3-substituted derivatives of 2-hydroxypropionanilides
-
A series of 3-(substituted thio)-2-hydroxypropionanilides and some corresponding sulfones and sulfoxides of general structure 7, in which R' is methyl or trifluoromethyl, were prepared and tested for antiandrogen activity. Members of the trifluoromethyl series (7,R' = CF3) generally exhibited partial androgen agonist activity whereas the members of the methyl series (7,R' = CH3) were pure antagonists. Lead optimization in the methyl series has led to the discovery of novel, potent antiandrogens, which are peripherally selective. One of these, (RS)-4'-cyano-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-3'-(trifd luoromethyl)propionanilide, 40 (ICI 176334), is being developed currently for the treatment of androgen-responsive benign and malignant disease.
- Tucker,Crook,Chesterson
-
p. 954 - 959
(2007/10/02)
-