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cases, a pharmacophore model of a nonpeptide lead (or series) may show similarity to that of a
pharmacophore model of a peptide ligand. Examples of such work are detailed below.
A. Peptidomimetics: Receptor Agonists and Antagonists
Page 571
Specific examples that illustrate peptide scaffold-and nonpeptide template-directed drug design
strategies are shown in Figure 8 and include μ-opioid endorphin (END) agonist, 29 [34]; thyrotropinreleasing
hormone (TRH) agonist, 30 [13]; fibrinogen (GPIIa/IIIb) antagonists, 31 [35] and 32 [36];
CCK A antagonist, 33 [37]; CCK B/gastrin antagonist, 34 [38]; endothelin antagonist, 35 [39]; growth
hormone secretagogue (GHRP), 36 [40]; somatostatin agonist (partial), 37 [41], substance-P (NK 1)
antagonists, 38 [42]; neurokinin-A (NK 2) antagonist, 39 [43]; and neurokinin-B (NK 3) antagonist, 40
[44]. For the most part, the above compounds have been advanced as the result of extensive structureactivity
studies and, typically, more focused structural studies (NMR) on a conformationally
constrained, linear or cyclic peptide lead or series. Such structure-conformation activity studies have led
to the development of pharmacophore models to guide iterative structure-based design strategies.
One example is that of integrin receptor gpIIb/IIIa antagonists that are structurally derived from the
tripeptide sequence Arg-Gly-Asp, which is common to gpIIb/IIIa protein ligands such as fibrinogen,
vitronectin, fibronectin, von Willebrand factor, osteopontin, thrombospondin, and the collagens [45]. As
shown in Figure 9, transformations of the linear peptide ligand Arg Gly-Asp-Phe by both peptide
scaffold (at the Arg-Gly backbone) modification and substitution of the Arg side chain by a benzamidine
moiety provided the peptidomimetic lead 31 that is active in vivo as an antiplatelet agent [35]. On the
other hand peptidomimetics such as 32 illustrate nonpeptide template-based design strategies derived
from iterative transformations of a cyclic peptide lead in which a
γ-turn about the Asp residue was implicated in a pharmacophore model for the bioactive conformation
[36]. Specifically, the benzodiazepinone substructure of 32 may effectively replace this predicted γ-turn
conformation about the Asp, and the N-Me-Arg replacement with piperidine moiety was also compatible
to high-affinity receptor binding.
A second example is that involving the use of a glucopyranoside nonpeptide template by Hirschmann
and coworkers [41, 46] for systematic functionalization to create novel peptidomimetics for the
somatostain (SRIF) and substance-P (NK 1) receptors. As illustrated in Figure 10, the cyclic hexapeptide
SRIF agonist provided a macrocyclic lead structure that was transformed to a glucopyranoside template
designed to substitute for a postulated β turn about the Tyr-D-Trp-Lys-Thr substructure of the parent
peptide ligand. The prototype
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