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O
O
H
H
H
H
O
H
H
OH
O
NHCO
2
Et
7
7
O
H
O
H
7
O
H
H
H
H
H
H
H
N
N
N
CF
3
CF
3
CF
3
52
41
35
Scheme 2.5
Initial synthesis of analogs that incorporate primary urethane at C7
proceeded from 35.
67
Table 2.5 Summary of in vitro and pharmacokinetic data for compound 53.
67
PAR-1 K
i
8.1 nM
O
H
H
NHCO
2
Et
47 nM,
a
25 nM
b
Inhibition of human platelet
aggregation (IC
50
)
O
Ca
21
transient assay (K
i
)
c
1.1 nM
H
H
Proliferation assay (K
i
)
d
13 nM
Me
Rat PK (oral):
e
AUC
(0
24 h)
,
C
max
, F;ivt
1/2
5.3 (mM
h),
0.67 (mM), 33%;
5.1 h
N
Monkey PK (oral):
f
AUC
(0
24 h)
, C
max
, F;ivt
1/2
10 (mM
h), 1.3 (mM),
86%; 13 h
F
53
(absolute chirality
)
SCH 530348
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.
e
Oral and intravenous (iv) dosing of HCl salt at 10mg kg
1
.
f
Oral and iv dosing of HCl salt at 1mg kg
1
. Vehicle for oral dosing: 0.4% methylcellulose; vehicle
for iv dosing: 20% hydroxypropyl-b-cyclodextrin.
Compound 53 showed potent inhibition of platelet aggregation induced by
either thrombin (IC
50
¼
47 nM) or haTRAP (IC
50
¼
25 nM). However, the
compound did not inhibit platelet aggregation induced by ADP, collagen, the
thromboxane mimetic 9,11-dideoxy-11a,9a-epoxymethanoprostaglandin F2a
(U46619), or a PAR-4 agonist peptide. In additional functional assays, com-
pound 53 inhibited thrombin-induced calcium transients and thymidine
incorporation in human coronary artery smooth muscle cells (HCASMC) with
K
i
values of 1.1 and 13 nM, respectively. Compound 53 did not affect clotting
parameters (PT and APTT), suggesting that its mechanism of action was not
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