Chemistry Reference
In-Depth Information
t-Bu
O
HN
Cl
t-Bu
OH
t-Bu
OH
Cl
Cl
t-Bu
t-Bu
O
N
HN
O
O
O
H
2
N
N
N
N
N
NH
S
NH
N
N
O
HO
N
N
O
N
Me
O
Et
Me
Et
Cl
Cl
7
5
6
4
Me
3(
FR 171113)
PAR-1 IC
50
(binding
assay) = 120 nM
PAR-1 IC
50
(binding
assay) = 52 nM
PAR-1 IC
50
(binding
assay) = 33 nM
PAR-1 IC
50
(binding
assay) = 74 nM
Inhibition of h-platelet
aggregation (TRAP-6)
IC
50
=150nM
(thrombin) IC
50
= 290 nM
Dose-depdendent inhibition of
thrombusinaguineapigcarotid
artery thrombosis model (induced
by FeCl
3
) after sc administration
Inhibition of h-platelet
aggregation (IC
50
):
TRAP-induced
= 300 nM
α
-thrombin-induced
= 700 nM
TRAP-6-induced
5-HT inhibition
IC
50
=230nM
Inhibition of h-platelet
aggregation:
(thrombin) IC
50
=540nM
Inhibition of h-platelet
aggregation:
(TRAP) IC
50
=575nM
(thrombin) IC
50
=1.5
M
μ
Figure 2.4
Examples of early small-molecule thrombin receptor (PAR-1) anta-
gonists.
60,61
inhibitory values. Modest inhibition was noted in platelet aggregation func-
tional assays using TRAP as the agonist, while the inhibitory effect on aggre-
gation induced by a-thrombin was weak. However, compound 4 was reported
to show a strong inhibitory effect in functional assays in human coronary artery
smooth muscle cells that measure calcium transients induced by a-thrombin
(3 nM) or a peptide agonist (TFLLRNPNDK-NH
2
,30mM), with IC
50
values
of 82 and 55 nM, respectively.
61
In a proliferation functional assay in human
coronary artery smooth muscle cells (hCASMC) that measured the incorpo-
ration of [
3
H]thymidine induced by a-thrombin or TRAP, compound 4 showed
apparent K
i
values of 88 and 32 nM, respectively. In contrast to platelets, where
the inhibition of any thrombin-induced effect was transient, inhibition of cal-
cium transients and thymidine incorporation in hCASMC mediated by
thrombin was sustained over the time course of the assay.
2.4.4 Himbacine-derived Thrombin Receptor Antagonists
While the early peptidomimetic and small-molecule thrombin receptor
antagonists provided useful tools for the study of the pharmacology of the
thrombin receptor, they did not advance into clinical development. A more
promising series emerged from the natural product himbacine 8 (Figure 2.5).
Himbacine is a complex alkaloid isolated from the bark of Galbulimima bel-
graveana, a tall growing species of white magnolia found in the northern
Queensland regions of Australia and nearby Pacific islands. In the early 1990's,
the antimuscarinic properties of himbacine were reported, which stimulated
synthetic efforts in several laboratories to identify analogs with selective anti-
muscarinic activity for the M
2
subtype as a cholinergic approach to treat the
symptoms of Alzheimer's disease. Our own efforts in this area culminated in a
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