Peptides mimetics

Use of D-amino acids in the synthesis of a hairpin loop portion from the CD4 receptor provides a stable CD4 receptor mimic, which blocks experimental allergic encephalomyelitis (144). This synthetic constmct is not simply the mirror image or enantiomer of the CD4 hairpin loop, but rather an aH-D-constmct in the reverse sequence, thus providing stereochemicaHy similar side-chain projections of the now inverted backbone (Fig. 11). This peptide mimetic, unlike its aH-L amino acid counterpart, is resistant to en2yme degradation. As one would expect, the aH-D amino acid CD4 hairpin loop, synthesi2ed in the natural direction, the enantiomer of the natural constmct, is inactive. 

Example 1 Oligomers of a-Amlnooxy Acids as Peptide Mimetics... 

The ring in oxadiazolinones 54 (R1 = 3-benzyloxyphenyl, CbzNH-L-leucine, R2 = H, Y = 0) in a reaction with hydrazine hydrate cleaved to afford product 55, which was then used in the syntheses of peptide mimetics <1998JME3923, 1999BMC599>. The reaction of oxadiazolinone 54 (R Fmoc, R2 = H, Y = 0) with primary... 

J. R. Damewood, Peptide mimetic design with the aid of computational chemistry in... 

Other potent peptide mimetic NS3 protease inhibitors have been reported that incorporate a serine trap on the C-terminal end of the peptide. Thus, the inhibitory activity of telaprevir (VX-950, 59), (7nM vs. NS3, 300 nM vs. the la replicon) is based on truncation of the polypeptide substrate, maximizing binding by alteration of amino acids at the scissile site, and capping both N- and C-terminal ends, the latter with a known dicarbonyl serine trap. This compound has exhibited impressive antiviral activity in animals, and showed a 4.4 log drop in viral load in genotype 1-infected patients in a Phase lb clinical trial [110]. Telaprevir is expected to enter Phase 3 clinical trials in 2007. Additional bicyclo-proline-based P2 tetrapeptides, represented by analog 60 (Kj = 22 nM), have been explored. Although the compounds are selective inhibitors of NS3, little or no cell-based replicon activity was reported, presumably due to poor cellular permeability [111-114], A diastereomer of telaprevir, has been reported to inhibit the replicon with an EC50 of 0.55 pM [115]. 

James R. Damewood, Jr., Peptide Mimetic Design with the Aid of Computational Chemistry. 

Other than RIF and Taxol, many other commonly used clinical drugs have also been shown to activate PXR. These include peptide-mimetic HIV protease inhibitors [53], the cholesterol-lowering lovastatin and the anti-inflammatory dexamethasone [54]. A more comprehensive analysis of the effect of commonly used clinical drugs on PXR activation has recently been published by Sinz and colleagues [55]. 

Anodic Amide Oxdations - New Routes to Constrained Peptide Mimetics... 

Much of the recent work on the use of anodic amide oxidation reactions has focused on the utility of these reactions for functionalizing amino acids and for synthesizing peptide mimetics [13]. For example, in work related to the cyclization strategy outlined in Scheme 3, the anodic amide oxidation reaction has been used to construct a pair of angiotensin-converting enzyme inhibitors [14]. The retrosynthetic analysis for this route is outlined in Scheme 4. In this work, the anodic oxidation reaction was used to functionalize either a proline or a pipercolic add derivative and then the resulting methoxylated amide used to construct the bicyclic core of the desired inhibitor. A similar approach has recently been utilized to construct 6,5-bicyclic lactam building blocks for... 

It is important to note that it is the anodic amide oxidation reaction that makes this approach to peptide mimetics possible by allowing for the selective... 

Macrocyclization of esters of allylglycine with diols has been successfully used to prepare derivatives of 2,7-diaminosuberic acid [861,864]. The latter are surrogates of cystine, and therefore of interest for the preparation of peptide mimetics. For unknown reasons protected allylglycine derivatives can not be directly dimerized by self metathesis [864]. However, catechol [864], ethylene glycol [861], and 1,2- or 1,3-di(hydroxymethyl)benzene derivatives [860] of allylglycine are suitable templates for the formal self metathesis of this amino acid via RCM. 

Figure 3. Discovery of Urotensin II GPCR antagonist by peptide mimetic approaches. 3D models of the NMR solution structure of cyclic peptide derivatives were used as templates for virtual 3D pharmacophore searches and resulted into non-peptidic hits. ° (Figure reproduced with permission from review of Klabunde and Messier. )...

Substmcture search of this backbone (smiles O = C(N(C)C1C)CN(C)C1=0) reveals several hundreds commercially available compounds, which likely have been synthesized by the above synthetic route [1]. This backbone can also be considered as a peptide mimetic by using a-amino acid derived isocyanide and amine components and will be of value for biological studies and for the discovery of hydrolysis resistant and biologically active peptide fragments (Fig. 6). 

A series of bi- and tricyclic pyridoazepine-type lactams was studied as conformationally restrained peptide mimetics acting as ACE inhibitors or dual inhibitors, that is both ACE and neutral endopeptidase (NEP) inhibitors, especially by the groups of Flynn and Robl. ACE and NEP are zinc metalloproteases acting as vasopeptidases. The respective inhibitors are used in the treatment of hypertension, congestive heart failure, and other cardiovascular diseases. 

M.R. Groves, Z.J. Yao, P.P. Roller, T.R. Burke Jr, D. Barford, Structural basis for inhibition of the protein tyrosine phosphatase IB by phosphotyrosine peptide mimetics. Biochemistry 37 (1998) 17773-17783. 

J. Gante, Peptide mimetics—tailor-made enzyme inhibitors, Angew. Chem. Int. Ed. 33(1994) 1699-1720. 

P. Wipf, T.C. Henninger, Solid-phase synthesis of peptide mimetics with ( )-alkene amide bond replacements derived from alkenylaziridines, J. Org. Chem. 62 (1997) 1586-1587. 

P. Cieplak, P.A. Kollman, Peptide mimetics as enzyme inhibitors Use of free energy perturbation calculations to evaluate isosteric replacement for amide bonds in a potent HIV protease inhibitor, J. Comput. Aided Mol. Des. 7 (1993) 291-304. 

Our research will further focus on the development of new and related methodologies for the investigation of interactions of carbon-bound fluorine in the context of peptide and protein environments. The rationalization of the properties of side chain-bound fluorine aims at the de novo design of peptides and peptide mimetics with new biological and pharmacological properties. 

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