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through direct inhibition of thrombin or other coagulation proteinases. The
compound was selective over a number of GPCRs, ion channels, and receptors.
Furthermore, it was inactive in the PAR-2, PAR-3 binding, and PAR-4 func-
tional assays.
The pharmacokinetics of 53 were studied in both rat and monkey models. In
rats, compound 53 displayed an elimination half-life of 5.1 h and an oral
bioavailability of 33%. In monkey, the compound exhibited a half-life of 13 h
and an oral bioavailability of 86%. Even at high concentrations (90 mM),
compound 53 did not show CYP450 inhibition potential, including metabo-
lism- and mechanism-based inhibition against various isozymes (CYP 1A2,
2C9, 2C19, 2D16, and 3A4) in human liver microsomes. Furthermore, the
compound showed a clean profile in a 14-day enzyme induction study in rats,
and mass balance studies using tritiated 53 gave full recovery of radioactivity
within the targeted period of seven days in both rat and monkey models. Due to
its excellent safety margin and superior potency, carbamate 53 (SCH 530348)
was advanced to clinical development.
2.4.4.2 Clinical Studies of SCH 530348
SCH 530348 demonstrated excellent safety and tolerability in Phase I clinical
studies. In pharmacodynamic platelet aggregation studies, the compound
showed a robust 490% inhibition of platelet aggregation at all tested doses for
a sustained period of time.
68
The target level of platelet aggregation throughout
the 28-day treatment period was maintained by a 2.5mg once-daily main-
tenance dose.
In a Phase II randomized double-blind placebo-controlled clinical study,
SCH 530348 was tested in patients who underwent non-urgent percutaneous
coronary intervention (PCI) in a trial known as Thrombin Receptor Antagonist
for Cardiovascular Event Reduction in Percutaneous Coronary Interventions
(TRA-PCI).
69-73
The primary endpoint was the bleeding risk associated with
SCH 530348 using the thrombolysis in myocardial infarction (TIMI) scale, and
the secondary endpoint was a composite of death or major adverse cardiac
events (myocardial infarction, urgent coronary revascularization, and ischemia
requiring hospitalization) in PCI patients who received a loading dose followed
by a 60-day maintenance dose of the drug. Patients also received other standard
therapies such as aspirin, clopidogrel, and anticoagulants.
For the primary safety endpoint, SCH 530348 was not associated with
increased TIMI major plus minor bleeding when compared with placebo. For
the secondary outcome endpoint, SCH 530348 was associated with a numerical
reduction in periprocedural myocardial infarction, although the study was not
powered to detect statistical significance. Overall, treatment with SCH 530348
reduced arterial thrombotic events without an increase in bleeding risk.
69
A key
sub-study to evaluate the inhibition of platelet aggregation showed that the
drug achieved a sustained, potent (480%) inhibition of TRAP-induced platelet
aggregation. Two additional Phase-II studies conducted in Japanese patients
(one in patients with acute coronary syndromes and the other in patients with
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