Peptidomimetics properties

Several other inhibitors of nonreceptor PTKs are currently in development but only a few of them are studied in clinical trials. Noteworthy, Dasatinib does not only inhibit c-Abl, but also potently blocks Src activity, a property that may contribute to its beneficial clinical effects in CML. Other kinase inhibitors being developed that inhibit c-Abl and/or Src are AZD-0530, AP-23994, PD-0183805, SU-6656, and Bosutinib (SKI-606). Furthermore, peptidomimetic SH2 domain inhibitors for Src, such as AP-22408 have been designed that decrease bone resorption and may be promising drugs to treat osteoporosis and other bone diseases, such as Paget s disease and osteolytic bone metastasis. 

The ability of these peptidomimetic collagen-structures to adopt triple helices portends the development of highly stable biocompatible materials with collagenlike properties. For instance, it has been found that surface-immobilized (Gly-Pro-Meu)io-Gly-Pro-NH2 in its triple-helix conformation stimulated attachment and growth of epithelial cells and fibroblasts in vitro [77]. As a result, one can easily foresee future implementations of biostable collagen mimics such as these, in tissue engineering and for the fabrication of biomedical devices. 

The domino process probably involves the chiral enamine intermediate 2-817 formed by reaction of ketone 2-813 with 2-815. With regard to the subsequent cy-doaddition step of 2-817 with the Knoevenagel condensation product 2-816, it is interesting to note that only a normal Diels-Alder process operates with the 1,3-bu-tadiene moiety in 2-817 and not a hetero-Diels-Alder reaction with the 1-oxa-l,3-butadiene moiety in 2-816. The formed spirocydic ketones 2-818/2-819 can be used in natural products synthesis and in medidnal chemistry [410]. They have also been used in the preparation of exotic amino adds these were used to modify the physical properties and biological activities of peptides, peptidomimetics, and proteins... 

Walter, E., Kissel, T., Reers, M., Dickneite, G., Hoffmann, D., Stuber, W., Transepithelial transport properties of peptidomimetic thrombin inhibitors in monolayers of a human intestinal cell line (Caco-2) and their correlation to in vivo data, Pharm. Res. 1995, 32, 360-365. 

A similar approach has been described by the same authors for the synthesis of related cyclic peptidomimetics [44]. A set often nucleophiles was employed for the substitution of the chlorine atom of the cyclic triazinyl-peptide bound to the cellulose membrane. By virtue of the aforementioned rate enhancement effects for nucleophilic substitution of the solid-supported monochlorotriazines, these reactions could be rapidly carried out by microwave heating. All products were obtained in high purity, enabling systematic modification of the molecular properties of the cyclic peptidomimetics. 

The central unit of these peptidomimetics imitates a /1-turn and brings the NH2-terminus of the cysteine analogue and the CO OH terminus of the methionine in spatial proximity these can then complex the Zn2+ ion which is essential for activity of the FTase [26]. The free acid 7 inhibits the enzyme with an IC50 value of 1 nmol/1, whilst in intact cells the methyl ester 8, despite its weaker in vitro activity, is significantly more potent because it can penetrate the plasma membrane better due to its lower polarity. This property can be used to convert the morphology of H-Ras-transformed cells back to the normal form and to inhibit growth of these cells, whereas the substance shows no effect on Src-transformed and untransformed rat fibroblasts. The inhibitor therefore acts selectively on transformed cells and does not influence growth of normal cells. This result is noteworthy because farnesylation of the wild type H-Ras protein... 

The past 3 years have seen tremendous advances in both the design of Cat K inhibitors and in our understanding of the effect of Cat K inhibition on bone remodeling. The structural diversity of Cat K inhibitors has expanded considerably from simple peptidomimetics to non-peptidic derivatives and even non-covalent inhibitors. The potency, selectivity and pharmacokinetic properties of key compounds are very attractive and seem well-suited to further development. The disclosure of clinical validation of the effect of Cat K inhibition on bone mineral density, plus the provocative data suggesting a decoupling of bone resorption and bone formation provides a compelling framework for further development of Cat K inhibitors for the treatment of osteoporosis. 

Ideally, a peptidomimetic agent should have one or more of the following properties (1) high specificity/ selectivity for a single receptor, (2) metabolic stability, (3) prolonged duration of action, (4) high receptor affinity and thus potency, (5) minimal adverse effects, and (6) good bioavailability. 

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. 

Unfortunately, direct Ugi reaction of 85 predominantly led to the formation of DHOPs (87) [172]. However, by applying a MCR-alkylation-MCR strategy, the Ugi products (88) could be isolated in high yields [173]. The obtained conformationally constrained peptidomimetics allow for unprecedented diversification and were ultimately evaluated for their turn-inducing properties, indicating an open turn structure for 88a (Fig. 27). 

Frecer, V., Berti, F., Benedetti, F., Miertus, S. Design of peptidomimetic inhibitors of aspartic protease of HIV-1 containing -Phe Psi Pro- core and displaying favourable ADME-related properties. J. Mol. Graph. Model. 2008, 27, 376-87. 

Thus, the monofluoroalkene moiety is a non-hydrolysable isostere of the pep-tidic bond, and hence can be used as a peptidomimetic unit in the design of protease inhibitors [59,60]. This type of rigid isosteres of the peptidic bond can facilitate the cisjtrans conformational control of the fragment replaced. Because of the double bond, the bond length and angles of the peptidic bond are suitably mimicked, and the fluorine atom complements the analogy for electronic properties. This approach has been developed in the case of prolylamide fragments, in... 

The potential utility of peptides as therapeutic agents with clinical applications is limited as a consequence of intrinsic peptide properties such as metabolic instability or poor transmembrane mobility. Hence, the design and synthesis of meta-bolically stable peptide analogs that can either mimic or block the bioactivity of natural peptides or enzymes is an important area of medicinal chemistry research. Numerous structural modifications to peptides have been examined in pursuit of molecules with more desirable properties [1-3]. These modified structures, peptidomimetics, are nonpeptide molecules that imitate the desired properties of the natural substances. 

Some peptides that contain peptidomimetic units IPICF = C] have been studied. Among them, prolylamides have exhibited the most striking results. The differences in the inhibition properties between the tetrapeptides with IPICF = CJPro and those with TiCH = CJPro as peptidomimetic units are significant. The trans conformation of the amide bond of a peptide is generally considered to be more stable than the cis... 

From all the peptidomimetic studies carried out so far, particularly on CCK-peptides, two stable analogues of tyrosine O-sulfate have emerged that apparently retain the properties for expression of the full bioactivity of the peptide analogues, i.e. 4-(sulfomethyl)phenylala-nine 121 and 4-(carboxymethyl)phenylalanine 122 shown in Scheme 17. 

Given the extensive biology associated with peptides, it is not surprising that considerable effort has been devoted to the synthesis of peptidomimetics to overcome the unfavorable properties and therapeutic deficiencies of peptides. In particular, since the advent of solid-phase synthesis and, more recently, combinatorial chemistry, interest in peptido-mimetic design and preparation has exploded. In theory, the peptide chemist is only limited by their imagination in the novel modifications that can be tailored for synthetic peptide analogues. 

Peptidomimetics have found wide application as biostable, bioavailable, and often potent surrogates of naturally occurring peptides. They form the basis of important families of enzyme inhibitors and they act as receptor agonists and antagonists. Peptide chemists are also gaining a deeper understanding of the structural features of this class of compounds that influence their ability to permeate biological membranes and their pharmacokinetic properties. 

However, it was immediately recognized by peptide chemists that, even in the cases where a direct (backbone)peptide -protein(backbone) interaction is not operative, the backbone conformation may dramatically influence the biological response. It is evident that the introduction of new, promising peptidomimetics is based primarily on the combined knowledge of the complementary conformational, topochemical, and electronic properties of the native peptide and of its address (in other words, of the receptor or the active site of the enzyme with which it interacts). Then, the design of peptidomimetics as potential bioactive compounds must take into particular account two structural factors (i) a favorable fit (tertiary structure) with respect to the corresponding complementary spatial situation at the active site (ii) the placement of structural elements (e.g., functional groups, polar and... 

As a topographically constrained analogue of tyrosine, p,2,6-trimethyltyrosine (TMT) offers many advantages for topographical design of peptide and peptidomimetic analogues due to its very well-defined conformational and dynamic properties. Examination of the yflyf en-... 

As in the case of the five-membered proline analogues, besides pipecolic acid (6) as the six-membered homologue of proline, related aza-, oxa-, and thia-analogues are used to mimic the conformationally restricting properties of proline in the peptidomimetic design of bioactive compounds.1202 ... 

The study of Saa has so far concentrated on their use as biopolymer building blocks to mimic oligo- and polysaccharide structures via amide bond linkages.1In 1994 the first example of a Saa as a new type of peptidomimetic [replacement of amino acid(s) by Saa] was reported/44 which was later extended to the Saa construction kit 7-16, and others, a versatile tool for the manipulation of peptide properties 45"51 (Scheme 2). 

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