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Vol. 30, Issue 11, 1288-1295, November 2002
Sanofi-Synthelabo Recherche, Toulouse cedex, France
Clopidogrel (SR25990C, PLAVIX) is a potent antiplatelet drug, which
has been recently launched and is indicated for the prevention of
vascular thrombotic events in patients at risk. Clopidogrel is
inactive in vitro, and a hepatic biotransformation is necessary to
express the full antiaggregating activity of the drug. Moreover, 2-oxo-clopidogrel has been previously suggested to be the essential key
intermediate metabolite from which the active metabolite is formed. In
the present paper, we give the evidence of the occurrence of an in
vitro active metabolite after incubation of 2-oxo-clopidogrel with
human liver microsomes. This metabolite was purified by liquid chromatography, and its structure was studied by a combination of mass
spectometry (MS) and NMR experiments. MS results suggested that
the active metabolite belongs to a family of eight stereoisomers with
the following primary chemical structure:
2-{1-[1-(2-chlorophenyl)-2-methoxy-2-oxoethyl]-4-sulfanyl-3-piperidinylidene}acetic acid. Chiral supercritical fluid chromatography resolved these isomers.
However, only one of the eight metabolites retained the biological
activity, thus underlining the critical importance of associated
absolute configuration. Because of its highly labile character,
probably due to a very reactive thiol function, structural elucidation
of the active metabolite was performed on the stabilized acrylonitrile
derivative. Conjunction of all our results suggested that the active
metabolite is of S configuration at C 7 and Z configuration at C 3-C
16 double bound.
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