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.
Novel steroidal pyrimidyl inhibitors of P450 17 (17α-hydroxylase/C17-20-lyase)
Haidar, Samer,Ehmer, Peter B.,Hartmann, Rolf W.
, p. 373 - 374 (2001)
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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.
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.
