Chemistry Reference
In-Depth Information
O
O
NCO
2
Et
HO
NCO
2
Et
O
NCO
2
Et
O
48
46
47
O
OBn
O
H
H
O
H
NCO
2
Et
NC
O
2
Et
O
H
O
H
H
H
H
H
O
O
OBn
50
49
O
H
H
8
CO
2
Et
N
O
A
H
C
PAR-1
K
i
= 4.7 nM
Ex vivo
platelet aggregation inhibition @ 24 h = 75%
a
Monkey PK (oral ):
F
= 62%
Enzyme induction study (8 days, mice ): clean
Mass balance study (1 mg kg
-1
, iv in cynomolgus
monkey ): clean
H
H
N
F
51
a
After an oral dose of 1 mg kg
-1
in cynomolgus monkey; agonist: TRAP.
Synthesis of heterocyclic analog 51 and its biological profile.
66
Scheme 2.4
bond acceptors would be interesting. However, at the outset, we had some
concerns about the hydrolytic stability of such a primary urethane. The
initial synthesis of 7-amino derivatives was carried out from an available
supply of 35 by sequential oxidation, reductive amination, and N-derivatiza-
tion (Scheme 2.5).
The primary urethane 52 had a PAR-1 K
i
of 13 nM. In the ex vivo platelet
aggregation inhibition assay, this compound showed complete ablation of
platelet aggregation for 424 h after a single oral dose of 1mg kg
1
. This result
promoted us to study the 7-amino series more thoroughly, and we investigated
amides, ureas, sulfonamides, and carbamates. Following the previously
established SAR for the pendant phenyl group, we also modified this sub-
stitution pattern. Together, these efforts lead to the identification of SCH
530348 (53) as our current development candidate.
67
Compound 53 showed a K
i
of 8.1 nM in the binding assay (Table 2.5).
Detailed binding studies were consistent with a competitive binding of 53 to the
PAR-1 receptor. Furthermore, compound 53 showed a long dissociation t
1/2
of
about 20 h, which may explain the superb ex vivo potency and long duration of
action for this compound.
Search WWH ::
Custom Search