Synthesis of stable isotope labelled internal standards for drug-drug interaction (DDI) studies.
The syntheses of stable isotope labelled internal standards of important CYP-isoform selective probes, like testosterone 1, diclofenac 3, midazolam 5, and dextromethorphan 7, as well as their corresponding hydroxylated metabolites 6β-hydroxytestosterone 2, 4'-hydroxydiclofenac 4, 1'-hydroxymidazolam 6 and dextrorphan 8 are reported. Microwave-enhanced H/D-exchange reactions applying either acid, base, or homogeneous and heterogeneous transition metal catalysis, or combinations thereof proved to be highly efficient for direct deuterium labelling of the above mentioned probes. Compared to conventional stepwise synthetic approaches, the combination of H/D exchange and biotransformation provides the potential for considerable time- and cost savings, in particular for the synthesis of the stable isotope labelled internal standards of 4'-hydroxydiclofenac 4 and 1'-hydroxymidazolam 6.
Isotope Chemistry & Metabolite Synthesis Department, Sanofi R&D, DSAR-DD, Industriepark Höchst, 65926 Frankfurt am Main, Germany. jens.atzrodt@sanofi.com
J
J
Atzrodt
J
J
Blankenstein
D
D
Brasseur
S
S
Calvo-Vicente
M
M
Denoux
V
V
Derdau
M
M
Lavisse
S
S
Perard
S
S
Roy
M
M
Sandvoss
J
J
Schofield
J
J
Zimmermann
D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D041961:Deuterium Exchange Measurement; D004008:Diclofenac / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D007553:Isotope Labeling / Q000379:methods*; D008872:Microwaves; D008874:Midazolam / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism; D012015:Reference Standards
D004364:Pharmaceutical Preparations; D004008:Diclofenac; D003577:Cytochrome P-450 Enzyme System; C040081:1-hydroxymethylmidazolam; C108036:4'-hydroxydiclofenac; D008874:Midazolam