Chemistry Reference
In-Depth Information
Table 11.1
Optimization of the isocytosine aryl region.
O
N
H
2
N
N
R
IC
50
(
m
M)
LE
Compound R
N
12
24
0.27
HN
13
51
0.27
14
6
0.28
O
Gln73
2.66
Thr72
2.90
3.07
2.72
3.30
Asp32
2.83
Asp228
Figure 11.11
Two views of the crystal structure of
14
-BACE complex. In the right-hand image,
residues 72-73 cover the ligand and have been removed for clarity.
11.7
Identification of the Dihydroisocytosine Series
Following the identification of
1
, a survey of structurally related compounds from the
company collection led to the identification of compound
15
(Figure 11.12). Binding of this
compound to BACE could be detected by NMR spectroscopy, but could not be quantitated
by SPR spectroscopy. Although the affinity was very weak, the compound was of interest
because the nonaromatic nature of the heterocycle made the overall structure significantly
different from that of the isocytosines. Despite the weak affinity, it could be crystallized
