Generate peptidomimetic

Both the LINK and the BOND constraints are ideal for specifying or excluding the chemistry at a particular bond. For example, one could easily exclude the formation of peptide bonds between specific components to generate peptidomimetics. However, the most prevalent use is to eliminate bonded heteroatoms or other unstable chemical species. 

This three-component coupling of a carbonyl, an amine and a hydrophosphoryl compound leads to a-aminophosphonates. The Kabachnik-Fields Reaction is very important in drug discovery research for generating peptidomimetic compounds. 

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... 

A range of 6-substituted 2-amino-e-caprolactams 66 has been synthesized by a sequence published by Robl et al. for investigating the generation of peptidomimetics. After Swern oxidation of the dipeptide 63, the corresponding... 

With this information in hand, initial attempts to generate BACE inhibitors used the peptidic Swedish variant substrate as a starting point and substituted the scissile amide bond with a statine. For example, Sinha et al. (1999) synthesized a P10-P4 1 Swedish variant peptide with a statine moiety in place of the Pl-Pl scissile bond and showed that this peptidomimetic displayed an IC50 of 40 pM for inhibition of BACE. Optimization of this inhibitor was then performed by systematic replacement of amino acid side chains. Replacement of the PE Asp residue by Val reduced the IC50 for BACE inhibition to 30 nM this inhibitor is referred to here as Stat-Val. 

A form of peptidomimetics (a peptidomimetic is a compound that acts as a substitute for peptides in their interaction with receptors) is the formation of DKPs where amino acid residues are cyclized to form a stable ring structure. The design and development of peptidomimetics allows for the generation of new pharma-cotherapeutic agents with the potential of exerting a more desirable or favorable physiological response than its prototype. ... 

Several groups tried to access medium-sized rings (ca. 8-12 membered) with peptide-like moieties. Most prominent is the I-MCR/RCM strategy [15, 16], As shown in Scheme 11. 12-Memhered cyclic peptidomimetics were reported hy Oikawa and co-workers who used initial Ugi-4CRs performed in excellent yields, followed hy functionalization of the resulting Ugi-platform to introduce the desired alkene functionalities [65]. RCM with the second generation Hoveyda-Gruhhs... 

Due to their substantial size and peptidic nature, inhibitors from this class were not suitable for clinical application. Nevertheless, the structural information derived from many crystal structures of peptidic inhibitors bound to the HIV PR active site was critical for subsequent modeling and design of the next generation of peptidomimetic and nonpeptidic inhibitors of HIV PR. 

Saquinavir, despite its distinct peptidomimetic character is a very potent inhibitor of HIV PR with an inhibition constant of 0.9 nMand an antiviral IC50 in vitro of 0.020 iM[ 10]. Although it suffers from a low oral bioavailability (5-10% in humans), it became an important starting point for the design of second generation, less-or nonpeptidic inhibitors. Saquinavir became the first HIV PR inhibitor approved by the FDA for treatment of AIDS. 

Libraries from Libraries Generation of Peptidomimetic Libraries... 

Fig. 1. Libraries from libraries. Generation of peptidomimetic libraries by chemical modification of an existing dipeptide library. (The same transformations were applied to longer peptides.)...

Hebach and Kazmaier reported the synthesis of cyclic peptidomimetics containing an alkylated amino acid via Ugi-4CR of N-terminal-protected aloc-amino acids, allyl isocyanoacetate, and chiral amines in trifluoroethanol. Allylic esters of tripeptides 193 were obtained in high yields and good stereoselectivity. Metathesis with 5% of Grubbs first-generation catalyst gave 16-membered cyclic peptides 194 in 30-50% yield (Scheme 2.69) [101]. 

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