Aspects of Peptidomimetics - Peptide and Protein Design for Biopharmaceutical Applications - page 62

When the benzo-substituted Tic isomers were used to replace the Tic
residue in TIPP, activity dropped considerably [89]. The 7-HO-Tic
residue was used in opioid peptides [72,81], and is present in the potent
and selective k-opioid antagonist JDTic [90] and in macrocyclic inhibi-
tors of HCV protease inhibitors [87], whereas 6-HO-Tic was used to
probe the topological requirements for substrate recognition by protein
tyrosine kinases [80]. Homologues of the Tic residue were prepared,
and when incorporated into the CCK 2 sequence, an interesting depen-
dence on the ring size was observed. The nine-membered analogue Nic
was equipotent to the parent Phe-containing compound [91].
Introduction of the Tcc residue in the bombesin sequence resulted in
potent antagonists [92].

R

R

NH

COOH H 2 N COOH

H 2 N COOH H 2 N

H 2 N COOH H 2 N COOH

R = H: Atc
R = OH: Hat

R = H: Aic
R = OH: Hai

Figure 3.14 Tetralin- and indane-constrained amino acids

The 2-aminotetralin-2-carboxylic acid (Atc) and its 6-hydroxy analo-
gue (Hat) have been used in opioid peptides (Figure 3.14) [72,93-96],
tyrosine kinase substrates [80], antigenic peptides [79], melanocortins
[97] and so on. A 6-phosphono-Atc analogue was used in Grb SH2
domain-directed tripeptides [98]. Conformational studies have indicated
that the (R)- and (S)-tetralin amino acids are significantly more helix-
promoting than Aib [99]. Recently, an asymmetric synthesis of this con-
strained residue has been published [100]. A solid-phase synthesis of the
equivalent tetrahydrocarbazole-constrained Trp analogue was devel-
oped, which could be upscaled to a multigram scale [101,102]. This
scaffold was used in the development of GnRH antagonists [101], neu-
romedin B partial agonists [103] and NK1/NK2 ligands [104].
The related achiral (when R ¼ H) indane-constrained amino acid (Aic)
and its chiral hydroxyl-substituted analogue (R ¼ OH, Hai) have also
frequently been used to probe the influence of the orientation of aromatic
amino acids [72,79,80,94,96,105]. Replacing Tyr 11 with Hai in the