154229-18-2Relevant articles and documents
Improved procedure for preparation of abiraterone acetate
Madhra, Mukesh Kumar,Sriram, Hari Mohan,Inamdar, Murad,Sharma, Mukesh Kumar,Prasad, Mohan,Joseph, Sony
, p. 555 - 558 (2014)
An improved procedure for the preparation of abiraterone acetate is described. The present process highlights reduced reaction time, isolation with acid-base treatment without involving column chromatography, multiple crystallization and is amenable to la
Application of trifluoromethanesulfonate in preparation of abiraterone acetate and synthesis method of trifluoromethanesulfonate
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Paragraph 0036-0045, (2021/06/12)
The invention particularly relates to application of trifluoromethanesulfonate in preparation of abiraterone acetate and a synthesis method. The invention provides a novel method for synthesizing abiraterone acetate. According to the method, a trifluoromethanesulfonate, such as iron trifluoromethanesulfonate and scandium trifluoromethanesulfonate, is adopted as a catalyst, isopropenyl acetate is adopted as an acylation reagent, and acetylation is carried out on the 3-site hydroxyl of abiraterone to synthesize abiraterone acetate. The method is simple to operate and high in product yield, and the use of irritant acetylation reagents such as acetic anhydride and acetyl chloride and chemical amounts of basic groups such as pyridine and triethylamine is avoided.
Abiraterone acetate preparation method
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Paragraph 0025-0039, (2020/03/06)
The invention provides an abiraterone acetate preparation method, which comprises: dissolving 17-iodoandrosta-5,16-dien-3 beta-hydroxyl and 3-pyridine zinc neopentanoate in an organic solvent, reacting at 50-80 DEG C for 3-12 h under the catalysis of a palladium catalyst, removing the solvent after the reaction is finished, and esterifying with acetic anhydride to obtain an abiraterone acetate product. According to the invention, the method overcomes the defects of expensive raw materials, high cost, harsh reaction conditions and the like in the prior art, is low in cost, mild in preparation conditions, simple and convenient in production method and suitable for industrial production, and has high application value.
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 (2020/09/04)
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.