Peptidomimetic Scaffolding

After the discussion of several approaches aimed at substituting the metaboli-cally unstable pTyr l,the following sections will introduce lead finding and opti- 

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Finally, Samuelsson and co-workers designed a new C2-symmetric HIV-PR inhibitor, on the basis of X-ray crystal structures, which indicated that the HIV protease existed as a C2-symmetric dimer. The peptidomimetic scaffold of this new class of inhibitors was based on D-mannitol and duplication of the C-terminus. Compounds 21 and 22 were rapidly synthesized and displayed comparable enzyme-inhibitory and antiviral potencies to Indinavir (Figure 24.4, Table 24.1).29-32... 

The virtual library was then generated by attaching the selected fragments to the peptidomimetic scaffold (Figure 4.2). 

Through systematic modification of the imidazole-appended 2-phenyl-aminobenzoate peptidomimetic scaffold (e.g., FTI-2148) a group at Abbott Pharmaceuticals have identified an expanded series of inhibitors that lack either the C-terminal Met carboxylate (as in compounds 14-23 of Ref. [55]) or the imidazole group (as in ABT-839) [56,70,71]. This latter compound became a clinical candidate and demonstrates that coordination to the zinc ion is not a prerequisite for potent inhibitors of FT. In place of metal-ligand (imidazole, thiol, etc.) coordination, ABT-839 exploits hydrophobic contact from the cyclohexylethyl and -butyl groups to the protein-binding pocket. For the structures of other CaaX peptidomimetics, please refer to Table 6.1. 

Trisubstituted 1,2,4-triazoles 215 were synthesized on solid-phase from various thioamides 214 and hydrazldes leading to peptidomimetic scaffolds <03OL4465>. 

The design and synthesis of antifungal analogs of the cyclic peptide rhodopeptin (36) (Fig. 15.16) illustrate a recent application of peptidomimetic scaffolding, where the structure of the biological target is not knovm. After structure-activity relationship (SAR) studies, the important side-chains of the peptide... 

The 2-azadiene system of the pyrazinone scaffold undergoes inter- and intramolecular cycloaddition reactions with a variety of (functionalized) alkenes forming bicyclic adducts, leading to the stereoselective generation of a variety of natural product analogues as well as peptidomimetics [58]. These bicyclic compounds could serve as key intermediates in the synthesis... 

Fragment screening by NMR was applied recently in the search of non-peptidic small molecule inhibitors. Two scaffolds (13) and (14), which bind the enzyme at the S1-S3 and the S2 binding site respectively, as shown by chemical shift perturbation, were linked together to yield competitive inhibitors such as (15) with micromolar IC50 values [158]. There have been no reports of non-peptidic inhibitors with potency and pharmacokinetics similar to the peptidic or peptidomimetic inhibitors described above. 

A similar scaffold for the preparation of peptidomimetics was prepared by Mitsunobu cyclization of the molecule coming from the coupling of 4-benzylprolinol and iV-nosyl(o-nitrobenzensulfonyl) tryptophan 316 (Scheme 41). A Mitsunobu cyclization occurred easily due to the acidity of the NH of the nosyl group that could be further selectively deprotected under very mild conditions. The so-formed bicyclic amine 317 can be further coupled with different amino acids to give compounds 318, employed in the search of a new somatostatin pharmacophore <2005BML4033>. 

They can serve as templates or useful scaffolds from which peptidomimetic drugs with enhanced activity can be designed. ... 

In the technique of post hoc design, a set of descriptors are built up by examination of a set of compounds active at a particular receptor family or sub-class. Normally, the set of drugs would be from a commercial database such as MDDR or the Merck Index, etc. and the descriptors would usually be substructural fragment or key based. One example would be the GPCR-PA+ sub-class referred to above, where BCUT descriptors have been used to aid the design of a focused library of aroimd 2000 compoimds based on 8 scaffolds. Libraries have also been constructed based on peptidomimetic principles as well as on the concepts of privileged structures. ... 

Abstract Piperazines and its congeners, (di)keto piperazines are valuable tools in drug discovery, providing a natural path for the process peptide > peptidomimetic > small molecule also called depeptisation. Moreover, they can provide molecular probes to understand molecular pathways for diseases of unmet medical need. However, in order to better understand the design of such value added compounds, the detailed understanding of scope and limitation of their synthesis as well as their 3D structures and associated physicochemical properties is indispensables. Isocyanide multicomponent reaction (MCR) chemistry provides a prime tool for entering the chemical space of (di)(keto)piperazines since not less then 20 different ways exist to access a diversity of related scaffolds. 

Fig. 6 2D and 3D structure of a peptidomimetic 2,5-DKP. The scaffold can undergo two intermolecular hydrogen bond, thus rendering it conformationally rigid... 

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-... 

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