Chemistry Reference
In-Depth Information
O
O
O
N
HN
HN
H
2
N
H
2
N
H
2
N
N
N
N
15
IC
50
>1000
m
M
16
138
m
M
LE
=
0.35
17
79
m
M
LE
=
0.35
Figure 11.12
Compound
15
was identified by similarity searching. Methylation of
the
heterocycle C6 position
(16)
and
N3
(17)
led to further improved analogs.
15
16
Figure 11.13
Comparison of crystal structures of BACE with
15
and
16
. Addition of the C6
methyl group in
16
reduces the presumed energetic penalty for the aryl substituent to adopt
the pseudo-axial geometry seen in the bound conformation and also makes van der Waals
contact with the enzyme.
with the enzyme (Figure 11.13). The resolution of the structure was relatively low, but
sufficient to show that the heterocycle adopted an envelope conformation with the pendant
phenyl group in a presumably disfavored pseudo-axial position.
[
42
]
Using semiempirical
methods with a continuous solvent model, calculations indicated that this pseudo-axial
orientation was 1.4 kcal mol
−
1
higher in energy than the pseudo-equatorial orientation.
We speculated that replacement of the methine hydrogen with methyl
(16)
would reduce
this energetic penalty and thereby improve binding affinity. Indeed, calculations on
16
showed that although the pseudo-axial orientationwas still disfavored, the energy difference
between the two forms was reduced to only 0.1 kcal mol
−
1
. We prepared
16
and showed
that the affinity improved substantially. Crystallographic analysis of this compound showed
that the binding orientation was exactly maintained and that the methyl group made good
van der Waals contact with the back surface of the binding pocket.
As described above, it was known that N3 methylation was favored for the isocytosine
series. The analogous compound in the dihydroisocytosine series
(17)
was then prepared
and this resulted in a further improvement in affinity (IC
50
79 M) and maintenance of high
ligand efficiency.
