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N
N
NH
N
N
N
O
O
O
O
O
O
Cl
Cl
Cl
Cl
Cl
Cl
3
4
5
N
N
N
N
N
NH
2
NH
O
O
S
O
O
Cl
Cl
Cl
Cl
Cl
Cl
6
7
8
Figure 3.7
Active conformation probe compounds.
A
B
Activator
C
Tyr 214
Arg 63
Val 62
H
H
N
N
Tyr 215
2.8 Å
Glucose
2.9 Å
N
O
S
41
Pro 66
Val 452
Figure 3.8
GK-GK activator complex crystal structure. A, the GK-GKA complex;
B, GKA binding site interactions; C, GK activator structure.
(Figure 3.9) could mimic the H-bond donor-acceptor interactions of the cis-
amide bond of the N-acylurea.
Thus, several phenylacetamides of various 2-amino N-containing hetero-
aromatic systems (azoles and azines) were evaluated as GK activators and
found to be active. We discovered a number of heterocyclic ring systems that
were capable of activating GK, the main requirement being the presence of a
lone pair-bearing nitrogen atom adjacent to the acylated heteroaromatic amino
group. The data for several of these are shown in Table 3.1 (compounds 10-18).
Since 2-aminothiazoles consistently proved to be highly potent, they were
employed in further optimization experiments. In addition, there was a wide
tolerance for substitution at the 4- and 5-positions of the thiazole rings, as
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