Chemistry Reference
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PAR-1 Ki = 11 nM
O
O
H
H
H
H
Inhibition of human platelet aggregation (IC
50
)
a
= 60 nM
OH
OH
O
7
O
7
Ca
+2
transient assay (Ki)
c
= 85 nM
H
H
monkey,
human
H
H
Me
Me
2'
Proliferation assay (Ki)
d
= 22 nM
N
N
rat
5'
Rat PK (oral):
F
= 80%
36
35
CF
3
Monkey PK (oral):
F
= 89%
CF
3
Induced by 15 µM haTRAP .
c
Inhibition of thrombin - stimulated Ca
+2
transient in HCASM.
d
Inhibition of
3
H thymidine incorporation in human coronary artery smooth muscle cells
(HCASM).
a
Figure 2.9
Profile of second-generation PAR-1 antagonist 35.
65
the molecule and lower its log P. Since the C
7
carbon was the ''hot-spot'' of
metabolism, we replaced it with oxygen, sulfur, and nitrogen atoms. The
syntheses of the derivatives were carried out using the intramolecular Diels-
Alder reaction protocol as before; Scheme 2.4 illustrates the synthesis of the
aza derivatives.
66
From this structure-activity relation study, the ethylurethane 51 was iden-
tified as a promising thrombin receptor antagonist. This compound
showed a PAR-1 anity of 4.7 nM in the binding assay. In the ex vivo platelet
aggregation inhibition assay, compound 51 was quite potent, completely
inhibiting platelet aggregation at earlier time points and showing a robust 75%
inhibition of platelet aggregation at the 24-h time point, after oral adminis-
tration of 1mg kg
1
. The compound showed excellent pharmacokinetics
in rat and monkey species, and it was clean in an eight-day enzyme induction
assay. More importantly, this compound showed good recovery in the mass
balance study in cynomolgus monkey. However, compound 51 showed solu-
bility issues that could not be satisfactorily addressed using formulation
techniques.
2.4.4.1.5 Fourth-generation Thrombin Receptor Antagonists: Discovery of
Vorapaxar (SCH 530348). Encouraged by the clean profile of ethylurethane
51, we decided to further pursue the modified
C
-ring amine derivatives. In
this context, the exocyclic C
7
-amine derivatives were pursued. Since the ear-
lier compound 35 that bears a hydroxyl group (a hydrogen bond donor) had
excellent solubility and pharmacokinetic properties, and the secondary ure-
thane 51 (a hydrogen bond acceptor, but not a donor) retained the potency
and showed good clearance pattern, we thought that an exocyclic primary
urethane that provides both a hydrogen bond donor and multiple hydrogen
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