Aspects of Peptidomimetics - Peptide and Protein Design for Biopharmaceutical Applications - page 67

Further antagonists obtained by reduction of an amide bond are col-
lected in Table 3.1. In other examples, however, amide bond reduction
maintained the agonist character of the parent peptides. This was the case
for somatostatin [130], CCK [130] neurotensin [133,134], bradykinin
[135], dynorphin [127,142] and xenin 6 [143].

Table 3.1 Antagonist peptides obtained by amide bond reduction

Peptide analogue Sequence

Gastrin [144] Boc-Trp-Leu C(CH 2 NH) Asp-Phe-NH 2

SP(6-11) [145] D-Nal-Phe-Phe-Gly-LeuC(CH 2 NH)Phe-NH 2

b-CM [146] Tyr-ProC(CH 2 NH)Phe-Pro-Gly-OH

Ile-Glu-Pro-Dpr-Tyr-Arg-Leu-ArgΨ(CH 2 NH)Tyr-NH 2

NPY(28-36) dimer [147]

Ile-Glu-Pro-Dpr-Tyr-Arg-Leu-ArgΨ(CH 2 NH)Tyr-NH 2

[Phe 1 C(CH 2 NH)Gly 2 ]nociceptin (1-13)NH 2 Nociceptin [148]

[Leu 14 C(CH 2 NH)Leu 15 ]BN
[D-Phe 6 , Leu 13 C(CH 2 NH)Cpa 14 ]BN(6-14)
[Leu 14 C(CH 2 NH)Leu 15 ]NMC

BN [129]
BN(6-14) [141]
Neuromedin C [149]

Reduced amide analogues of endomorphin 1 and 2 were shown to be
partial agonists with significant in vivo antinociceptive action [150].
The discovery by Szelke in 1982 that the reduction of a Leu-Leu amide
bond in an octapeptide sequence of equine angiotensinogen increased the
inhibitory potency for renin 10 000-fold came at the start of the successful
use of amide bond isosteres in the design of transition-state analogue enzyme
inhibitors [151]. The tetrahedral geometry of this isostere resembles the
transition state for peptide bond hydolysis, as was shown for the binding
of a C(CH 2 NH) inhibitor to Rhizopus chinensis [152]. This isostere was
later used in the design of inhibitors of HIV protease [153], farnesyl trans-
ferase [154] and b-secretase [155]. However, it was never as successful as
other isosteres such as the hydroxyethyl isostere or the hydroxyethylamine
isostere, which will be discussed below. Whereas many of the peptide bond
modifications shown in Figure 3.17 result in an increased flexibility of the
main chain due to the removal of the partial double bond character of the
amide function, its replacement by an alkene - C(CH ¼ CH) - perfectly
maintains the trans geometry.Inordertomimicthe cis amide bond geome-
try, Z-alkene isosteres have been prepared, mainly to mimic cis -Xxx-Pro
amide bonds. However, the alkene function does not reproduce the polar