Biomedical Engineering Reference
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peptides. This 3D arrangement of the
D
-Trp and Lys residues has been the
basis for the design of a number of scaffolds that mimic this arrangement
of the critical side chains (Figures 3.44-3.50).
The design of the somatostatin mimetic, based on the b-
D
-glucose
scaffold by Hirschmann and coworkers, was a landmark in this field
[334] (Figure 3.44). The structure-activity relationships in this series
correlates with the one found for the cyclic peptides. Unexpectedly,
these glucose-based mimetics also showed affinity for the NK1 receptor
[335,336]. Replacement of the 2-benzyl substituent by an imidazol-4-
ylmethyl group improved affinity, and further incorporation of a pyridyl-
3-ylmethyl substituent at position 4 resulted in a potent analogue that
was also selective for the sstr4 receptor, and was no longer recognized by
the NK1 receptor.
Iminosugar-based scaffolds provided low-affinity analogues
[337,338]. More recently, catechol was used as a minimal scaffold to
display three of the somatostatin pharmacophores, resulting in mM affi-
nity for sstr2 and sstr4 [339]. The compounds shown in Figure 3.45 all
contain scaffolds that were designed as mimics for the b-turn conforma-
tion of the cyclic peptides, and display the important Trp and Lys phar-
macophores and one or two additional aromatic groups [340-344].
Whereas most of these mimetics showed mM affinities, the cyclic
thioether analogue was shown to be a sstr5-selective ligand with nM
potency [343].
NH
NH
2
NH
2
O
H
N
N
N
N
N
O
O
O
HN
O
NH
N
HN
O
O
O
NH
2
O
NH
N
NH
S
N
O
H
3
C
O
HN
N
O
N
O
NH
2
O
NH
2
Figure 3.45 Molecular scaffolds in somatostatin peptide mimetics
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