Clopidogrel, structure

Clopidogrel bisulfate has several related compounds that are to be impurity species [2, 6, 7]. The molecular structures of these impurities are shown in Fig. 2.12. 

FIGURE 2.12 Structures of four known impurities of clopidogrel bisulfate. 

Mohan et al. [8] used an NMR spectroscopic method to characterize impurity D in samples of clopidogrel bisulfate. The method entailed XH NMR (at 400.13 MHz) and 13C NMR (at 100.62 MHz), with a sample concentration of 1 mg/ml in DMSO-t/f, (this solvent also served as an internal chemical shift standard). It was found that the 1H NMR spectrum of impurity D exhibited one hydrogen band than did that of clopidogrel, while the 13C NMR and DEPT135 NMR spectra indicated the presence of one methyl carbon, two methylene carbons, eight methine carbons, and five quaternary carbons. This corresponded to a similar structure as for clopidogrel, but with one less methylene carbon and one more methine carbon. 

Ticlopidine is a thienopyridine antiplatelet agent, similar in structure and mechanism of action to clopidogrel. It has been shown to reduce the risk of stroke by 30% compared with placebo and by 21% compared with aspirin 325 mg/day inpatients at risk. The use of ticlopidine has been severely restricted by its side-effect profile, however. It causes bone marrow suppression, rash, diarrhea, and elevation of the serum cholesterol concentration. Neutropenia occurs in up to 2% of patients and generally is reversible. More problematic, however, is the increased risk of aplastic anemia and thrombotic thrombocytopenic purpura. Ticlopidine 250 mg twice daily is stiU available as an alternative in patients who fail or are intolerant of other therapies but is rarely needed. 

Although ticlopidine has the same mechanism of action as clopidogrel and possesses a similar molecular structure, the results of clinical trials among the two agents are strikingly different. The Swedish Ticlopidine Multicenter Study (STIMS) had determined that ticlopidine therapy (500 mg/day) was able to reduce total mortality in comparison to placebo in patients with intermittent claudication p =... 

Figure 7.3. The mechanism proposed for P450 bioactivation of the thiophene in tienilic acid to a reactive species that binds covalently to the protein (the protein nucleophile is denoted by Protein-XH). The structures of two other thiophene-containing drugs, ticlopidine and clopidogrel, that might be similarly activated are also shown.

Potential toxicity arising from the furan and thiophene ring structures is a concern in designing potential drug leads, but potential leads should not be eliminated on those grounds alone. The success of current pharmaceuticals that contain furan and thiophene moieties is a clear indication that ftiran- and thiophene-containing therapies can be made safe, and even exploited as in the case of clopidogrel. 

Enantioenriched tertiary a-aryl carbonyls represent an important class of organic compounds. They are prevalent structural motifs in many biologically active molecules and pharmaceuticals such as naproxen and clopidogrel. They are also important intermediates in the synthesis of many medicinally important molecules. 

Fig. 5.16 The pathway for the bioactivation of clopido-grel by P450s Clo, clopidogrel 2 oxo, 2-oxo-clopidogrel. The numbers shown in the structure of the active metabolite (AM) indicate the numbering of the two chiral centers...

Observational studies Cross-reactivity between clopidogrel and ticlopidine, which are structurally very similar, has been studied by reviewing the medical records of 76 patients who had an allergic or hematological adverse reaction to either drug and who were subsequently given the other [154. In 14 patients who had allergic or... 

Pereillo J, Maftouh M, Andrieu A, Uzahiaga M, Fedeli O, Savi P, Pascal M, Herbert J, Maffrand J, Picard C. Structure and stereochemistry of the active metahohte of clopidogrel. Drug Metab. Dispos. 2002 30 1288-1295. 

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