piperidines and thienopyridine

Antiplatelet drugs have an established place in the prevention of vascular events in a variety of clinical conditions, such as myocardial infarction, stroke and cardiovascular death. Both European and American guidelines recommend the use of antiplatelet drugs in patients with established coronary heart disease and other atherosclerotic disease. In high-risk patients, such as those with post-acute myocardial infarction (AMI), ischaemic stroke or transient ischaemic attack, and in patients with stable or unstable angina, peripheral arterial occlusive disease or atrial fibrillation, antiplatelet treatment may reduce the risk of a serious cardiovascular event by approximately 25%, including reduction of non-fatal myocardial infarction by 1/6, non-fatal stroke by 1/4 and cardiovascular death by 1/6. Some data indicate that antiplatelet drugs may also have a role in primary prevention. In people who are aged over 65 years, or have hypertension, hypercholesterolaemia, diabetes, obesity or familial history of myocardial infarction at young age, aspirin may reduce both cardiovascular deaths and total cardiovascular events. Aspirin has been studied and used most extensively. It may exert its beneficial effect not only by acting on platelets, but also by other mechanisms, such as preventing thromboxane A2 (TXA2)-induced vasoconstriction or reducing inflammation. Indeed, experimental data show that low-dose aspirin may suppress vascular inflammation and thereby increase the stability of atherosclerotic plaque. Moreover, in human studies, aspirin seems to be most effective in those with elevated C-reactive protein levels. Vascular events, however, do occur despite aspirin administration. This may be due to platelet activation by pathways not blocked by aspirin, intake of drugs that interfere with aspirin effect or aspirin resistance. In the CAPRIE (Clopidogrel vs. Aspirin in Patients at Risk of Ischaemic Events) study, long-term clopidogrel administered to patients with atherosclerotic vascular disease was more effective than aspirin in reducing the combined risk of ischaemic stroke, myocardial infarction or vascular death. In the setting of coronary stenting, a double regimen including aspirin and ticlopidine or clopidogrel has proved more effective in the prevention of in-stent thrombosis than aspirin alone. Chronic oral administration of the inhibitors of platelet membrane receptor GP IIb/IIIa has been largely disappointing.

Topics: Aspirin; Benzamidines; Clopidogrel; Coronary Artery Disease; Humans; Myocardial Infarction; Oximes; Piperidines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Pyridines; Stroke; Ticlopidine; Treatment Outcome

Tipidogrel (3), an effective anti-platelet drug candidate working by irreversibly inhibiting P2Y12 receptor, holds great promise in overcoming clopidogrel resistance and increasing bioavailability. As a prodrug like other thienopyridines, it metabolizes through thiophene ring opening to form active metabolites 3a and 3b, nevertheless they are easily to form disulfide bond. Derivatization of 3a and 3b via alkylation with MPBr can prevent disulfide conjugation and ensure reliable pharmacokinetic results. Thus, in order to support its pre-clinical studies on efficiencies in the formation of tipidogrel active metabolites, 13a and 13b were synthesized via seven steps of chemosynthesis and incubation with MPBr in rat plasma in vitro. The resulting crude productions were purified by semi-preparative HPLC to give Z configuration 13a and E configuration 13b. In LC-MS/MS spectra, they showed identical fragmentation pattern and retention time with M-13a and M-13b, the MPBr-derivatives of active metabolites of tipidogrel in rats. Thus, 13a and 13b were the anticipated alkylated active metabolite of tipidogrel. In addition, in the nucleophilic substitution of thioacetate with compound 11, besides the anticipated compounds 12a and 12b, their isomers compounds 12c and 12d were detected, whose structures were confirmed and the corresponding mechanism was presented.

Topics: Alkylation; Animals; Chromatography, High Pressure Liquid; Clopidogrel; Half-Life; Piperidines; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Pyridines; Rats; Receptors, Purinergic P2Y12; Tandem Mass Spectrometry; Thiophenes; Ticlopidine