Abstract
The metabolism of our prototypical thrombin receptor antagonist 1, Ki = 2.7 nM, was studied and three major metabolites (2, 4, and 5) were found. The structures of the metabolites were verified independently by synthesis. Compound 4 was shown to be a potent antagonist of the thrombin receptor with a Ki = 11 nM. Additionally, compound 4 showed a 3-fold improvement in potency with respect to 1 in an agonist-induced ex-vivo platelet aggregation assay in cynomolgus monkeys after oral administration; this activity was sustained with 60% inhibition observed at 24 h post-dose. Compound 4 was highly active in functional assays and showed excellent oral bioavailability in rats and monkeys. Compound 4 showed a superior rat enzyme induction profile relative to compound 1, allowing it to replace compound 1 as a development candidate.
MeSH terms
-
Animals
-
Biological Availability
-
Cytochrome P-450 Enzyme System / biosynthesis
-
Furans / chemical synthesis*
-
Furans / pharmacokinetics
-
Furans / pharmacology
-
Heterocyclic Compounds, 3-Ring / chemical synthesis*
-
Heterocyclic Compounds, 3-Ring / pharmacokinetics
-
Heterocyclic Compounds, 3-Ring / pharmacology
-
Humans
-
In Vitro Techniques
-
Macaca fascicularis
-
Microsomes, Liver / drug effects
-
Microsomes, Liver / enzymology
-
Platelet Aggregation / drug effects
-
Platelet Aggregation Inhibitors / chemical synthesis*
-
Platelet Aggregation Inhibitors / pharmacokinetics
-
Platelet Aggregation Inhibitors / pharmacology
-
Pyridines / chemical synthesis*
-
Pyridines / pharmacokinetics
-
Pyridines / pharmacology
-
Radioligand Assay
-
Rats
-
Receptors, Thrombin / antagonists & inhibitors*
-
Stereoisomerism
-
Structure-Activity Relationship
Substances
-
Furans
-
Heterocyclic Compounds, 3-Ring
-
Platelet Aggregation Inhibitors
-
Pyridines
-
Receptors, Thrombin
-
decahydro-7-hydroxy-3-methyl-4-(2-(5-(3-(trifluoromethyl)phenyl)-2-pyridinyl)ethenyl)naphtho(2,3-c)furan-1(3H)-one
-
Cytochrome P-450 Enzyme System