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O
O
O
9a
9a
O
O
O
3
3
3
3a
3a
Me
R
R
R
15
R=CO
2
Bn
A
B
exo
exo
O
O
O
H
H
H
8a
9a
9a
O
O
O
3a
3a
3a
3
4a
3
3
4
4
H
H
CO
2
Bn
4
H
H
CO
2
Bn
H
H
Me
Me
Me
CO
2
Bn
16
21
(not formed)
Figure 2.6
The high diastereoselectivity of the IMDA can be explained by an A
1,3
strain-induced conformational preference and the exo-selective nature of
the cyclization. Conformation B is preferred due to A
1,3
strain. The pre-
ferred conformation dictates the facial selectivity of C3a-C9a bond for-
mation, rendering a cis relationship between the C3 methyl and C3a
hydrogen. The relative stereochemistry between C3a and C9a is controlled
by the exo-selective transition state.
high diastereoselectivity. By employing optically pure IMDA precursor 11,this
synthesis translates to an enantiospecific construction of the tricyclic ring system.
2.4.4.1.1 Structure-Activity Relationship (SAR) Studies. Key points of the
SAR studies of himbacine-derived PAR-1 antagonists are shown in
Table 2.3.
59,64
A small alkyl group such as methyl or ethyl is preferred at the
C
6
0
position of the pyridine (9 and 22). However, alkyl substitution at C
5
0
is not favored (23 versus 9 or 10). The substituted pyridine can be replaced
with a 2-vinylisoquinoline (e.g., 28). Although phenyl substitution is not
tolerated at C
6
0
(e.g., 24), it is highly desirable at C
5
0
(e.g., 25). More impor-
tantly, the C
5
0
aryl derivatives showed markedly improved rat oral absorp-
tion relative to the C
6
0
alkyl-substituted derivatives.
The lactone ring is essential for PAR-1 activity. The corresponding ring-
opened hydroxy acid (not shown) is unstable and undergoes spontaneous ring
closure to the lactone. Reduced versions of the lactone, such as lactol (26) and
the fused tetrahydrofuran (27), are far less active. The C
3
methyl group is
optimal: while C
3
-unsubstituted lactone (29) and C
3
gem-dimethyl substituents
are tolerated, larger substituents at C
3
are not tolerated (e.g., 31). The internal
double bond within the tricyclic unit does not affect the PAR-1 anity
(structure type B). However, the trans-disubstituted vinyl group that links the
tricyclic unit to the heteroaryl group is essential for activity. Reduction of this
double bond resulted in greater than 10-fold loss in potency (data not shown).
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