1940176-03-3Relevant articles and documents
The 16,17-double bond is needed for irreversible inhibition of human cytochrome P45017α by abiraterone (17-(3-pyridyl)androsta-5,16-dien-3β- ol) and related steroidal inhibitors
Jarman,Barrie,Llera
, p. 5375 - 5381 (1998)
Abiraterone (17-(3-pyridyl)androsta-5,16-dien-3β-ol, 1) is a potent inhibitor (IC50 4 nM for hydroxylase) of human cytochrome P45017α. To assist in studies of the role of the 16,17-double bond in its mechanism of action, the novel 17α-(4-pyridyl)androst-5-en-3β-ol (5) and 17β-(3- pyridyl)-16,17α-epoxy-5α-androst-3β-ol (6) were synthesized. 3β- Acetoxyetienic acid was converted in three steps into 5 via photolysis of the thiohydroxamic ester 8. Oxidation of an appropriate 16,17-unsaturated precursor (21) with CrO3-pyridine afforded the acetate (23) of 6. Inhibition of the enzyme by 1, the similarly potent 5,6-reduced analogue 19 (IC50 5 nM), and the 4,16-dien-3-one 26 (IC50 3 nM) and by the less potent (IC50 13 nM) 3,5,16-triene 25 is slow to occur but is enhanced by preincubation of the inhibitor with the enzyme. Inhibition following preincubation with these compounds is not lessened by dialysis for 24 h, implying irreversible binding to the enzyme. In contrast under these conditions the still potent (IC50 27 nM) 17α-(4-pyridyl)androst-5-en-3β-ol (5) showed partial reversal after 5 h of dialysis and complete reversal of inhibition after 24 h. This behavior was also shown by the less potent 16,17-reduced 3-pyridyl compounds 3 and 24. Further, in contrast to the compounds (1, 19, 25, 26) with the 16,17-double bond, the inhibition of the enzymic reaction was not enhanced by preincubation either with 5 or with the 17β-pyridyl analogues 3, 4, and 24 which also lack this structural feature. The results show that the 16,17- double bond is necessary for irreversible binding of these pyridyl steroids to cytochrome P45017α. However oxidation to an epoxide is probably not involved since epoxide 6 was only a moderately potent inhibitor (IC50 260 nM).
Abiraterone acetate reducing impurity and preparation method thereof
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, (2017/10/22)
The invention discloses an abiraterone acetate reducing impurity and a preparation method thereof. The impurity is 17-(3-pyridyl) androstane-3 beta-acetoxyl. The preparation method of the impurity includes the steps: taking dehydroepiandrosterone as a starting material; performing catalytic hydrogenation by palladium carbon to obtain (3 beta)-3-hydroxy-17-sterone; performing reaction by hydrazine hydrate to obtain 17-hydrazono-androstane-3 beta-alcohol; performing iodine substitution to obtain 17-iodine-androstane-3 beta-alcohol; reacting the 17-iodine-androstane-3 beta-alcohol with borane reagents under palladium catalysis to obtain 17-(3-pyridyl) androstane-3 beta-alcohol; performing acetic anhydride acetylation to obtain the abiraterone acetate reducing impurity 17-(3-pyridyl) androstane-3 beta-acetoxyl.
ALTERING STEROID METABOLISM FOR TREATMENT OF STEROID-DEPENDENT DISEASE
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Page/Page column 45, (2016/09/26)
A method of treating steroid-dependent disease such as prostate cancer in a subject is described that includes administering a therapeutically effective amount a CYP17A inhibitor and an effective amount of a 5- -reductase inhibitor to the subject.
