RT Journal Article
SR Electronic
T1 Structure and Stereochemistry of the Active Metabolite of Clopidogrel
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1288
OP 1295
DO 10.1124/dmd.30.11.1288
VO 30
IS 11
A1 Pereillo, Jean-Marie
A1 Maftouh, Mohamed
A1 Andrieu, Alain
A1 Uzabiaga, Marie-Francoise
A1 Fedeli, Olivier
A1 Savi, Pierre
A1 Pascal, Marc
A1 Herbert, Jean-Marc
A1 Maffrand, Jean-Pierre
A1 Picard, Claudine
YR 2002
UL http://dmd.aspetjournals.org/content/30/11/1288.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics