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C. Rigidification
Page 330
The number of conformations that a peptide can adopt in solution is reduced by cyclization. This can be
optimized, at least in theory, to lock the peptide in the conformation that has the highest affinity for the
receptor, resulting in a gain of affinity, primarily for entropic reasons. The structures of the fungal
aspartic proteinases reveal that the binding cleft is a wide channel with no obvious division between the
pockets, e.g., S 1 and S 3 are contiguous. The bound structures of numerous inhibitors have shown that
alternate side chains are in van der Waals contact due to the extended conformation that these ligands
adopt. In addition, at certain positions, e.g., P 2, the side chains are allowed very different conformations
due to the permissiveness of the pocket. Hence, the cross-linking of certain side chains may, at least, not
be detrimental to inhibitory potency and may also reduce the susceptibility to degradation in the gut or
plasma. It might therefore be expected that oligopeptide renin inhibitors would be suitable' candidates
for cross-linking experiments. A similar philosophy of rigidification was pursued in the development of
the ACE inhibitor cilazapril [37].
A number of statine-containing inhibitors possessing disulphide links between P 2 and P 5, and P 2 and P 4'
have been synthesized [13] although the best potencies were slightly less than for the linear peptides. An
alkyl cycle of varying length was introduced between the hydroxyl of a serine residue at P 1 and the main
chain nitrogen of P 2 in a series of reduced-bond inhibitors [53]. Potencies similar to the uncrosslinked
molecule were achieved but none were greater. This was attributed to the cis isomerisation of the P 3—P 2
peptide bond giving a conformation that cannot fit the active site of the enzyme. Difficulties in
achieving more potent cyclic inhibitors may be due to the tight binding environment provided by some
pockets (especially S 1 and S 3), and the possibility that other unproductive conformations of the inhibitor
become favorable. More recently similar findings have been reported for cyclic analogs of pepstatincontaining
alkyl crosslinks of variable length between the P 1 and P 3 side chains [38].
D. In Vivo Stability
Peptides, when administered orally, are susceptible to degradation in the stomach by gastric enzymes
and the proteinases of the pancreas and brush border of the small intestine. Their lifetimes in the plasma
are often short due to rapid proteolysis and other metabolic processes. Early efforts were made to
improve the resistance of renin inhibitors to hydrolysis in vivo by the use of blocking groups at the N-
and C-terminii [39] and replacement of susceptible peptide bonds other than the renin cleavage site.
Studies of SAR have shown that various N- and C-terminal groups, some based on the morpholine
nucleus and derivatives of it, have a favorable effect on the duration of inhibition in the
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