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Amide bond isosteres

The discovery of yet other nonhydrolyzable amide bond isosteres has particularly impacted the design of protease inhibitors, and these include hydroxymethylene or FfCF OH)], 12 hydroxyethylene or T fCF OFQCFy and T fCFkCHiOH)], 13 and 14, respectively dihydroxyethylene or ( [ )], 15, hydroxyethylamine or 4 [CH(0H)CH2N], 16, dihydroxyethylene 17 and C2-symmetric hydroxymethylene 18. In the specific case of aspartyl protease inhibitor design (see below) such backbone modifications have been extremely effective, as they may represent transition state mimics or bioisosteres of the hypothetical tetrahedral intermediate (e.g., xF[C(OH)2NH] for this class of proteolytic enzymes. [Pg.564]

The first synthesis of r j[NHCH2] containing pseudopeptides was described in 1989. This reduced retro-amide bond isostere was presumed by molecular graphic analysis to provide potential protease inhibitors. A complete study of the conformational effects by modifying the amide link with [NHCHj] was reported. 86,871... [Pg.415]

Table 4. Inhibition of FTase In Vitro and In Vivo by CaaX Analogues Incorporating an Olefin Amide Bond Isostere... Table 4. Inhibition of FTase In Vitro and In Vivo by CaaX Analogues Incorporating an Olefin Amide Bond Isostere...
Based on these considerations, four distinct types of peptidomimeticshave been identified to date (9,10). The first invented were structures that contain one or more mimics of the local topography about an amide bond (amide bond isosteres). Strictly speaking, these are properly classified aspseudopeptides (11), but in recent years, they have been called peptidomimetics on occasion. For historical reasons, we classify the peptide backbone mimetics as type I mimetics (Table 15.1). These... [Pg.635]

The replacement of amide bonds by retro-in-verso amide replacements (71, 72) and other amide bond isosteres generates pseudopeptides (11). This process was first used to stabilize peptide hormones in vivo and later to prepare transition state analog (TSA) inhibitors. Systematic efforts to convert good in vitro inhibitors into good in vivo inhibitors became the driving force for further development of peptidomimetics. Figure 15.17 illustrates some of the peptide backbone modifications that have been made in an effort to increase bioavailability. Replacement of scissile amide (CONH) bonds with groups insensitive to hydrolysis (e.g., CHaNH) has been extensively practiced. Reviews of this work have appeared (11,73). Removal of the proton donors and... [Pg.644]

Studies on IC50 data of hydroxyethylene-based isostere derivatives (41) reported by Thompson et al. [161] gave QSAR 49 [14]. Most of the compounds in this dataset were hydroxyethylene-based HlVPl containing heterocychc Pl -P2 amide bond isostere derivatives. X-substituents were either keto or hydroxyl group whereas Y were mainly alkyl. [Pg.226]

Jones RCF, Ward GJ (1988) Amide bonding isosteres imidazolines in pseudopeptide chemistry. Tetrahedron Lett 29 3853-3856... [Pg.362]

Choy N, Choi H, Jung WH, Kim CR, Yoon H, Kim SC, Lee TG, Koh JS (1997) Synthesis of irreversible HIV-1 protease inhibitors containing sulfonamide and sulfone as amide bond isosteres. Bioorg Med Chem Lett 7(20) 2635-2638. doi 10.1016/S0960-894X(97)10054-3... [Pg.239]

The metabolic stability of peptides is generally relatively low, which can be a drawback for therapeutic use. Approaches to increase the metabolic stability include backbone modifications, such as the introduction of amide bond isosteres (e.g., sulfonamides), N-alkylation, incorporation of nonproteinogenic or D-amino acids, and the use of dialkylated amino acids. More recently, the replacement of amide bonds with triazole isosteres has also become a viable strategy to modify... [Pg.148]

Fig. 1. FTase inhibitors in which amide bonds were replaced by isosteric amines and ethers, and which incorporate non-natural amino acids... Fig. 1. FTase inhibitors in which amide bonds were replaced by isosteric amines and ethers, and which incorporate non-natural amino acids...
Synthesis of funtionalized (Z)-fluoroalkene-type dipeptide isosteres (36) via Sml2-mediated reduction of y,y-difluoro-ot, -enoates 2.3.19. Reductive formation of fluoroolefins and subsequent conversion to diketopiperazine mimics (71). Nonpeptidic amide bond replacement... [Pg.700]

FLUOROOLEFIN DIPEPTIDE ISOSTERES 2.1. Alkenes as amide bond substitutes... [Pg.702]

Electrostatic potential surfaces of Gly-Gly and the fluoroolefin isostere created with B3LYP/6-31G by using Titan 1.0.5 (Fig. 5) illustrates that reduced polarization of the fluoroolefin relative to the amide bond. The original postulates described above were confirmed in independent findings from two groups [14,44] (Fig. 5). [Pg.704]

As a prelude to the use of olefination reactions to introduce the fluoroolefin amide isostere, the synthesis of fluoroolefin analogs of CGP 49823 is described where a nonpeptidic amide bond was replaced with a fluoroolefin [55]. Comparison of the binding affinities of these analogs for the NK1 receptor enabled determination of the active conformation of the amide containing compound CGP 49823. It was otherwise not easy to establish that the syn orientation of the aromatic ring of the benzamide towards the 2-benzyl substituent was the active conformation (Scheme 10). [Pg.709]

And most importantly for a discussion of the replacement of amide bonds by fluoroolefin isosteres, the cis and trans amide bonds have different hydration shells [43,85]. The role of solvation and desolvation is understood to be crucial not only in amide bond isomerization but also in peptide transport generally. [Pg.722]

Tertiary amides, such as those associated with prolyl amide bonds frequently influence turn architectures. The importance of the cis Xaa-Pro bond on activity was recognized and proposed to be the source of differentiation in biological activity [86] therefore, isomerization of the prolyl amide bond is central to regulation of protein folding, immunosuppression, and mitosis. These functions are not surprisingly associated with several disease states and thus substitution of the acyl-proline amide bond with the fluoroolefin isostere has received considerable attention. [Pg.722]

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. [Pg.732]

The simplest approach to isosteric replacement of one or both sulfur atoms of the cystine disulfide with a methylene or ethylene moiety is given for natural bioactive peptides when one cysteine residue is located in the N-terminal sequence position and the related amino group or peptide extension is not involved in the bioactivity. This allows for direct side chain to backbone (N-terminus) cyclization via amide bonds with suitable 5-carboxyalkyl derivatives of the second cysteine residue, or with the oo-carboxy group of aminodicarboxylic adds containing an alkyl side chain that mimics the Ca to Ca spacer in cystine. Thereby, the length and degree of branching of the sulfide or alkyl spacer can additionally be varied. [Pg.224]

Cyclic peptides have been synthesized not only for the purpose of improving biological activities and selectivity, but also to explore basic features of secondary structures in peptides and to investigate with such mimetic compounds the conformational behavior of proteins. For this purpose artificial building blocks have been frequently used or amide bonds have been modified isosterically. Nature also offers a variety of modifications in cyclic peptides that are critically involved in their bioactivity. Some of the most common natural and synthetic modifications including unusual structural elements such as thiazoles (and dihy-drothiazoles) and oxazoles (and dihydrooxazoles) with broad synthetic applications will be presented in the following section. [Pg.517]


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Amide bonds

Amides: , bonding

Fluoroalkenes as isosteres of the amide bond

Isostere

Isosteres

Isosteric

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