Nonpeptide templates

Figure 7 A novel, phosphate ester linking strategy [22] was used in the synthesis of phenyl phosphate-containing compound libraries, accomplished in 96-deepwell reaction blocks [23], Rigid, nonpeptide templates (A-group) and pY+3 substituents (B-group) satisfied the diversity sites of the molecules.

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 (NKj) receptors. As illustrated in Figure 10, the cyclic hexapeptide SRIF agonist provided a macrocyclic lead stmcture that was transformed to a glucopyranoside template designed to substitute for a postulated 3 turn about the Tyr-D-Trp-Lys-Thr substructure of the parent peptide ligand. The prototype... 

Peptide scaffold- and nonpeptide template-based design strategies ... 

The above examples of peptide scaffold- or nonpeptide template-based peptidomimetic agonists or antagonists illustrate various strategies to elaborate bioactive conformation and/or pharmacophore models of peptide ligands at their receptors. In many cases, receptor subtype selectivity has also been achieved by systematic structural modifications of prototypic leads of peptidomimetics. Thus, although the 3D structures of G-protein-coupled receptors (GPCRs) remain as elusive (except for models constructed from homology-based low-... 

Specific examples of peptidomimetics which illustrate peptide scaffold- and nonpeptide template-directed drug-design strategies as applied to protease in-... 

An example of the signal-transduction protein-targeted inhibitor design which illustrates both peptide scaffold- and nonpeptide template-based approaches is that for the Ras famesyl transferase inhibitor discovery. Such compounds show potential as new therapeutic agents for Ras-related carcinogenesis [81]. Substrate sequences for famesyl transferase have the consensus Cy s-A A, - A A2-Met motif (AA refers to Val or lie). Both substrate-based... 

Figure 13 Series of de novo designed nonpeptides containing a benzamide template (exemplified by compound 12, AP21 733) designed to interact favorably with Src SH2 and specifically to displace structural waters found in complexed Src SH2 structures [14,27]. The Src SH2 binding IC50 is shown for each compound, as well as a comparative IC50 for Ac-pTyr-Glu-Glu-lle-NH2 (compound 9).

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