Chemistry Reference
In-Depth Information
O
O
O
O
H
H
O
O
O
Br
O
HO
O
O
O
O
O
Me
H
H
38
CO
2
Bn
39
Me
COOH
40
O
H
H
O
O
O
H
H
H
H
7
OH
OH
O
O
7
7
O
H
H
Me
H
H
H
H
Me
Me
2'
+
N
2'
N
N
5'
5'
CF
3
CF
3
CF
3
41
35
PAR-1 IC
50
=17nM
(PAR-1 Ki = 11 nM)
36
PAR-1 IC
50
=23nM
O
O
H
O
OH
O
O
H
H
H
H
H
H
8
8
O
O
O
O
H
H
H
H
O
O
Me
H
H
O
O
Me
Me
Br
+
H
O
2'
N
N
N
43
42
5'
CF
3
45
CF
3
34
CF
3
44
PAR-1 IC
50
=41nM PAR-1IC
50
=28nM
Scheme 2.3
Synthesis of 7- and 8-hydroxyl derivatives.
65
hepatocytes. On the contrary, the a-OH isomer 35 did not undergo conversion
to the b-OH isomer under the same conditions. This interconversion profile was
reversed in rat (Figure 2.9). The favorable metabolic stability of 35 in cyno-
molgus monkeys and in human liver hepatocytes prompted us to select this
compound as a replacement for 33.
In a multiple rising-dose enzyme-induction study in rat for eight days,
compound 35 showed an excellent therapeutic window with no sign of auto-
induction. However, in a later mass balance study in cynomolgus monkeys, the
targeted recovery of radioactivity could not be achieved within the required 10
days after intravenous administration of [
3
H]-35. This raised concerns about
insucient clearance and the potential for the compound to persist within the
body for a prolonged period of time, resulting in the discontinuation of the
development of the second-generation development candidate 35.
2.4.4.1.4 Third-generation Thrombin Receptor Antagonists. The next phase
of lead optimization efforts was directed to incorporating heteroatoms into
the
C
-ring of the tricyclic skeleton in order to increase the overall polarity of
Search WWH ::
Custom Search