115375-60-5Relevant articles and documents
Slow-, tight-binding inhibition of CYP17A1 by abiraterone redefines its kinetic selectivity and dosing regimen
Cheong, Eleanor Jing Yi,Nair, Pramod C.,Neo, Rebecca Wan Yi,Tu, Ho Thanh,Lin, Fu,Chiong, Edmund,Esuvaranathan, Kesavan,Fan, Hao,Szmulewitz, Russell Z.,Peer, Cody J.,Figg, William D.,Chai, Christina Li Lin,Miners, John O.,Chan, Eric Chun Yong
, p. 438 - 451 (2020)
Substantial evidence underscores the clinical efficacy of inhibiting CYP17A1-mediated androgen biosynthesis by abiraterone for treatment of prostate oncology. Previous structural analysis and in vitro assays revealed inconsistencies surrounding the nature and potency of CYP17A1 inhibition by abiraterone. Here, we establish that abiraterone is a slow-, tight-binding inhibitor of CYP17A1, with initial weak binding preceding the subsequent slow isomerization to a high-affinity CYP17A1-abiraterone complex. The in vitro inhibition constant of the final high-affinity CYP17A1-abiraterone complex ( ( Ki? = 0.39 nM )yielded a binding free energy of -12.8 kcal/mol that was quantitatively consistent with the in silico prediction of 214.5 kcal/mol. Prolonged suppression of dehydroepiandrosterone (DHEA) concentrations observed in VCaP cells after abiraterone washout corroborated its protracted CYP17A1 engagement. Molecular dynamics simulations illuminated potential structural determinants underlying the rapid reversible binding characterizing the two-step induced-fit model. Given the extended residence time (42 hours) of abiraterone within the CYP17A1 active site, in silico simulations demonstrated sustained target engagement even whenmost abiraterone has been eliminated systemically. Subsequent pharmacokineticpharmacodynamic (PK-PD) modeling linking time-dependent CYP17A1 occupancy to in vitro steroidogenic dynamics predicted comparable suppression of downstream DHEA-sulfate at both 1000- and 500-mg doses of abiraterone acetate. This enabled mechanistic rationalization of a clinically reported PK-PD disconnect, inwhich equipotent reduction of downstreamplasma DHEAsulfate levels was achieved despite a lower systemic exposure of abiraterone. Our novel findings provide the impetus for reevaluating the current dosing paradigmof abiraterone with the aim of preserving PD efficacy while mitigating its dose-dependent adverse effects and financial burden. SIGNIFICANCE STATEMENT With the advent of novel molecularly targeted anticancer modalities, it is becoming increasingly evident that optimal dose selection must necessarily be predicated on mechanistic characterization of the relationships between target exposure, drug-target interactions, and pharmacodynamic endpoints. Nevertheless, efficacy has always been perceived as being exclusively synonymous with affinity-based measurements of drug-target binding. This work demonstrates how elucidating the slow-, tight-binding inhibition of CYP17A1 by abiraterone via in vitro and in silico analyses was pivotal in establishing the role of kinetic selectivity in mediating time-dependent CYP17A1 engagement and eventually downstream efficacy outcomes.
Green Suzuki coupling reaction for synthesis of abiraterone acetate and its analogues
Bian, Xiaoqin,Wang, Lizhong,Liu, Jinliang,Wang, Cunde
, p. 289 - 292 (2016)
An eco-friendly efficient method was developed for the synthesis of abiraterone acetate and analogues in water-PEG-400 (6:1; v/v) at 75°C from various arylboronic acids and 17-(trifluoromethanesulfonyl)oxy-3β-acetoxylandrosta-5,16-diene obtained from the 3-acetate of dehydroepiandrosterone.
Steroid derivative and preparation method thereof
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Paragraph 0070-0076, (2020/05/02)
The present invention relates to a steroid derivative and a preparation method thereof. The molecular structure of chlorambucil is improved on the basis of chlorambucil, the excellent anticancer curative effect of the core structure of chlorambucil is combined with the branched chain structure of a steroid parent nucleus with a good physiological activity effect to form a unique novel targeted anti-leukemia drug with a novel structure; when the steroid derivative is used for preparing an antitumor drug, the synthesis process and the preparation process are optimized, so the solvent consumptionis reduced, and the environment is protected; and the prepared drug reduces the clinical potential safety hazard.
Preparation method for abiraterone acetate intermediate
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Paragraph 0026-0031, (2019/01/08)
The invention discloses a preparation method for an abiraterone acetate intermediate. The preparation method includes adding 4.2 mL of triethylamine and 5 g of composite oxide into a suspension liquidof 10 g of a raw material compound and 120 mL of dichloromethane at 0 DEG C; diluting 5.6 mL of trifluoromethanesulfonic anhydride by using 50 mL of the dichloromethane to slowly drop to the above-mentioned solution; performing stirring reaction on the mixture at room temperature for 12 hours; adding 100 mL of water, performing stirring to quench the reaction, extracting 3 times by using 3-fold volume of the dichloromethane, merging organic phases, performing washing successively by using 100 mL of 2N hydrochloric acid and 100 mL of a saturated salt solution, and performing drying through sodium sulfate and condensing so that a crude product can be obtained; and obtaining an abiraterone acetate intermediate after purifying by flash column chromatography. The composite oxide can be effectively used for catalyzing and synthetizing the abiraterone acetate intermediate. The preparation method inherits the advantages of the prior art of being convenient and less in step, and significantlyenhances yield.
Structure-Based Design of Inhibitors with Improved Selectivity for Steroidogenic Cytochrome P450 17A1 over Cytochrome P450 21A2
Fehl, Charlie,Vogt, Caleb D.,Yadav, Rahul,Li, Kelin,Scott, Emily E.,Aubé, Jeffrey
, p. 4946 - 4960 (2018/06/20)
Inhibition of androgen biosynthesis is clinically effective for treating androgen-responsive prostate cancer. Abiraterone is a clinical first-in-class inhibitor of cytochrome P450 17A1 (CYP17A1) required for androgen biosynthesis. However, abiraterone also causes hypertension, hypokalemia, and edema, likely due in part to off-target inhibition of another steroidogenic cytochrome P450, CYP21A2. Abiraterone analogs were designed based on structural evidence that B-ring substituents may favorably interact with polar residues in binding CYP17A1 and sterically clash with residues in the CYP21A2 active site. The best analogs increased selectivity of CYP17A1 inhibition up to 84-fold compared with 6.6-fold for abiraterone. Cocrystallization with CYP17A1 validated the intended new contacts with CYP17A1 active site residues. Docking these analogs into CYP21A2 identified steric clashes that likely underlie decreased binding and CYP21A2 inhibition. Overall, these analogs may offer a clinical advantage in the form of reduced side effects.
Steroid compound and preparation method thereof
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Paragraph 0048, (2017/10/13)
The invention relates to a steroid compound impurity in production of abiraterone acetate. The steroid compound is 17-(ethyl)androsta-5,16-diene-3beta-ol acetate (as shown in a formula I which is described in the specification). A preparation method for the steroid compound comprises the following steps: reacting sulfonic acid ester of dehydroisoandrosterone acetate with diethyl(3-pyridyl)borane; then carrying out reduced-pressure distillation and separation so as to obtain an intermediate 17-(ethyl)androsta-5,16-diene-3beta-ol; and then carrying out acetylation so as to obtain the steroid compound. The steroid compound as shown in the formula I can be applied to qualitative and quantitative research on and detection of impurities in raw abiraterone acetate.
Method for Preparing Abiraterone Acetate
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Paragraph 0036, (2016/09/26)
A method for preparing abiraterone acetate. The steps are: dehydroepiandrosterone acetate and trifluoromethanesulphonic anhydride undergo a sulfonylation reaction under the catalysis of an organic base to obtain a compound as represented by formula II; the compound is reacted with a 3-pyridine organoboron compound or a 3-pyridine organosilicone compound under the catalysis of Bis(triphenylphosphine) palladium(II) dichloride to obtain a crude abiraterone acetate product; the crude product is recrystallized in a protic or aprotic solvent to obtain an abiraterone acetate crystal; the crystal is further put into a solvent which easily dissolves the crystal and dissolved under heating, and the solution is dropwise added into a solvent which does not easily dissolve the crystal until a solid is precipitated under stirring, such that a micro powder abiraterone acetate is obtained; and the solvent which easily dissolves the crystal is a mixture of any two or more of acetone, ethanol and water, and the solvent which does not easily dissolve the crystal is water. The method has a rational route, a simple and convenient operation, a good product quality, and a high yield. No column chromatography, and salt-formation are required in the entire process to satisfy requirements of industrial scale productions. Furthermore, an abiraterone acetate particle size of about 10 um is obtained.
A process for the purification of abiraterone acetate
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Paragraph 0008; 0025, (2017/02/09)
The present invention provides a purifying method for abiraterone acetate. According to the method, phosphoric acid is adopted as a salt forming reagent to react with a abiraterone acetate crude product to obtain a light yellow crystal, wherein the light yellow crystal is the abiraterone acetate phosphate, is easily filtered, and has the purity more than 98%, the abiraterone acetate phosphate can be used for the next reaction without further purification to prepare the abiraterone acetate, and the purity of the abiraterone acetate prepared by freeing can be more than 98%; the purification process is simplified, the production cost is reduced, and the method is suitable for industrial production.
Abiraterone acetate oxalate and method for purification of abiraterone acetate
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Paragraph 0031; 0032, (2017/04/08)
The invention relates to an abiraterone acetate oxalate and a purification method of abiraterone acetate. Oxalate and an abiraterone acetate crude product are subjected to a reaction to obtain abiraterone acetate oxalate; and then the abiraterone acetate oxalate is subjected to a dissociation reaction to obtain abiraterone acetate.
INHIBITORS OF CYP17A1
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Paragraph 0098, (2016/04/05)
Compounds according to formula I or II are provided. Such compounds are useful in treating cancers, such as leukemia, colon cancer, breast cancer, or prostate cancer by beneficially inhibiting CYP17A1. Pharmaceutical compositions and methods including the compounds are also provided.
