Peptidomimetics design inhibitors

An outstanding example in peptidomimetic design evolved from these studies. Truncation and conformational restriction of a reduced isostere of the parent peptide substrate, followed by systematic replacement of the peptide-like side-chains provided the potent non-peptidic inhibitor (111)(Fig. 15.46) (207). This approach highlights the transition from a peptide-derived structure to a compound with no apparent resemblance to the original peptide. 

The design of peptidomimetic HLE inhibitors by researchers at Zeneca Pharmaceuticals23-2Z as based largely on information obtained from the X-ray crystal structures of peptidic inhibitors bound to HLE and the closely related enzyme, porcine pancreatic elastase (PPE). These two enzymes show relatively high structural homology, especially in the active site region. 

Subsequent to these peptidomimetic design efforts, X-ray crystal structures were obtained of inhibitors from the 3-amino-pyridin-2-one and 5-amino-pyrimidin-6-one classes complexed to These experimental... 

Furthermore, peptidomimetic SH2 domain inhibitors for Src, such as AP-22408 have been designed that interfere with effector binding and thereby disrupt signal transduction. AP-22408 decreases bone resorption in animal studies and may be a promising drug to treat osteoporosis and other bone diseases, such as Paget s disease and osteolytic bone metastasis. 

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 idea for macrocydic peptidomimetic inhibitors of PDF originated from the structure of the reverse hydroxamate BB-3497 that was reported by Clements et al. [73]. On this basis, Hu et al. [81] designed the cyclic compound 135, in which a nonyl group serves as the cross-linked Pi and P3 side chain, as depicted in Fig. 8. 

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. 

D. F. (1998). Stmcture-based design of cathepsin K inhibitors containing a benzyloxy-substituted benzoyl peptidomimetic. /. Med. Chem. 41,3923-3927. 

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... 

Small-molecule inhibitors of caspases would have obvious use as therapeutics. The current medicinal chemistry research literature is rich in studies attempting to achieve this important design goal. In early work, both reversible and irreversible peptide-based inhibitors of various caspases have been developed. Peptidomimetic ketones were also devised for example, acyloxymethyl ketones were designed and developed as potent, time-dependent irreversible caspase inhibitors. 

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. 

An interesting concept for designing specific HIV PR peptidomimetic inhibitors with internal two-fold symmetry was first formulated by John Erickson and his colleagues from Abbott Laboratories [28]. 

Recent communications from Bristol-Myers Squibb [14,15] describe peptidomimetic inhibitors (Figure 7) that were designed to bind thrombin with an N- to C-polypeptide chain sense opposite that of the substrate and form interactions similar to those made by the first three residues of hirudin ( 1, Thr2, Tyr3). In the x-ray crystal structure of BMS-183507 (K = 17.2 nM) with thrombin [15], the N terminus is facing the catalytic site while the methyl ester is... 

Wu T-P, Yee V, Tulinsky A, Chrusciel R, Nakanishi H, Shen R, Priebe C, Kahn M. The structure of a designed peptidomimetic inhibitor complex of oc-thrombin. Protein Engineering 1993 5 471-478. 

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