Aspects of Peptidomimetics - Peptide and Protein Design for Biopharmaceutical Applications - page 63

NT(8-13) sequence resulted in a partial inverse agonist that was selective
for the hNTR2 versus the hNTR1 receptor [106]. The 1-substituted
isomers of Atc and Aic, which can be considered as constrained phenyl-
glycine analogues, have also been used as rigid templates in modified
peptides [97].
The azepine-constrained Phe (Aba, Figure 3.12) was originally devel-
oped by Flynn [107] and de Laszlo [108] for the design of ACE and renin
inhibitors, ultimately leading to highly potent dual ACE/NEP inhibitors
[109,110]. Later, this heterocycle was also used in farnesyl transferase
inhibitors [111] (Figure 3.15).

NC

COOH NH

O

N

N

N
H

N

N
H

Cl

N

R ′

O

SH

O N

H

R

N

O

dual ACE/NEP inhibitor farnesyl transferase inhibitor

Indolo-azepine analogue: Aia

Figure 3.15 Azepine-constrained peptide analogues

Several synthetic methods leading to this type of constrained Phe
or Tyr analogue have been developed [107,108,111-114]. When this
type of fixation was used as a constrained Phe 3 residue in the opioid
peptide dermorphin, it was able to shift the selectivity from the m-to
the d-receptor [81]. In the N-terminal dermorphin tetrapeptide, the
replacement of both Tyr 1 and Phe 3 by the corresponding Hba and
Aba residues resulted in a highly constrained analogue that was
showntohavepotent in vivo analgesic effects when administered
intrathecally as well as intravenously [114]. Further applications of
this constraint include the melanocortin analogue MT-II [115],
bradykinin [116] and opioid dipeptide analogues [114,117-119]. A
related spiro-Aba analogue was shown to effectively induce a b-turn
[120], and when incorporated into the HOE140 sequence resulted in
a potent bradykinin B2 antagonist [116]. The equivalent indole-con-
strained analogue (Aia, Figure 3.15) can easily be prepared [121],
and was used to prepare selective somatostatin peptide mimetics
[122] (see Figure 3.47).
A large number of other constrained amino acids have been described
in the literature. A comprehensive discussion would be beyond the scope
of this chapter. However, the general principles which underly the design
of many of these analogues have been discussed here in order to make it