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O
O
H
H
H
H
O
B
F
3
C
O
O
O
H
H
H
H
Me
Me
Suzuki reaction
2
′
2
′
N
N
5
′
X
32
X=OTf
33
CF
3
Scheme 2.2
Representative synthesis of orally bioavailable C5
0
-aryl derivatives.
59
Table 2.4 Summary of in vitro and pharmacokinetic data for compound 33.
PAR-1 K
i
2.7 nM
Inhibition of human platelet aggregation (IC
50
) 44 nM,
a
24 nM
b
Ca
21
transient assay (K
i
)
c
O
H
H
2.6 nM
O
Proliferation assay (K
i
)
d
13 nM
H
H
Rat PK (oral): F
30%
Me
Monkey PK (oral): F
50%
2
′
N
5
′
33
CF
3
a
Induced by 10 nM thrombin.
b
Induced by 15 mM haTRAP.
c
Inhibition of thrombin-stimulated Ca
21
transient in HCASM.
d
Inhibition of [
3
H]thymidine incorporation in HCASM.
30%. The oral bioavailability of 33 in cynomolgus monkey was 50%; the half
life after intravenous administration in e. monkey was 12.4 h.
The effect of 33 on TRAP-induced ex vivo platelet aggregation in whole
blood in conscious, fasted cynomolgus monkeys was determined. Following
oral administration, the compound showed dose-dependent inhibition of pla-
telet aggregation for the duration of the experiment (6 h), with complete sup-
pression of platelet aggregation at or above a dose of 3 mg kg
1
. This
compound did not affect clotting parameters (PT, prothrombin time, and
APTT, activated partial thromboplastin time), confirming that its mechanism
of action is not by active site inhibition of thrombin or other coagulation
proteases. The compound was inactive in the PAR-2 and PAR-4 functional
assays, and was selective against a number of GPCRs,
ion-channels, and
receptors that it was tested against.
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