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Synthesis of [D 4 ]‐ and [D 7 ]‐4 β ‐hydroxycholesterols for use in a novel drug–drug interaction assay
Author(s) -
Turley Wesley A.,
Burrell Richard C.,
Bonacorsi Samuel J.,
Goodenough Angela K.,
Onorato Joelle M.
Publication year - 2012
Publication title -
journal of labelled compounds and radiopharmaceuticals
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 47
eISSN - 1099-1344
pISSN - 0362-4803
DOI - 10.1002/jlcr.1952
Subject(s) - chemistry , cyp3a , drug , yield (engineering) , cytochrome p450 , chromatography , silver acetate , drug metabolism , pharmacology , enzyme , biochemistry , organic chemistry , medicine , materials science , metallurgy
Cytochrome P450 3A (CYP3A) enzymes are involved in the metabolism of over half of today's prescription drugs. As a result, drugs metabolized by CYP3A have a risk of drug–drug interactions (DDIs). Recent studies have shown the potential to use 4 β ‐hydroxycholesterol as an endogenous biomarker of CYP3A activity and predictor of potential DDIs. Bristol–Myers Squibb has developed a liquid chromatography‐electron ionization‐tandem mass spectrometry method that accurately measures 4 β ‐hydroxycholesterol levels in clinical plasma samples following treatment with a CYP3A inducer or inhibitor. Stable isotope labeled (SIL) [D 4 ]‐ and [D 7 ]‐4 β ‐hydroxycholesterols were synthesized to assist in the development of this new quantification method. The SIL analogs were prepared from the appropriate [D 4 ]‐ or [D 7 ]‐cholesterol starting material in two steps. The labeled cholesterols were oxidized with bromine and silver acetate in pyridine to give an acetate protected hydroxy group at C4. Hydrolysis of the acetate protecting group provided [D 4 ]‐ and [D 7 ]‐4 β ‐hydroxycholesterols in 15%–28% overall yield. 4 α ‐Hydroxycholesterol was also required during method development and was prepared in four steps from cholesteryl benzoate in 1% overall yield.