Peptidomimetics protease inhibitors

Type III mimetics represent the Farmer definition ofpeptidomimetics in that they possess novel templates, which appear unrelated to the original peptides but contain the essential groups, positioned on a novel non-peptide scaffold to serve as topographical mimetics. Several type III peptidomimetic protease inhibitors have been characterized where direct... 

Tipranavir The FDA recently granted approval for tipranavir, the first member of a new class of nonpeptide inhibitors of the HlV-1 protease, in combination therapy. Although it also binds to the active site of the HlV-1 protease, tipranavir differs in structure from previously available peptidomimetic protease inhibitors and retains activity against HIV-1 isolates that are resistant to other HIV protease inhibitors. Tipranavir, coadministered with ritonavir, is approved for the treatment of HIV-1-infected adults with evidence of viral replication and who have received multiple treatment regimens or have HlV-1 strains resistant to multiple protease inhibitors. As noted in a black box ... 

Boceprevir 129 (Victrelis, Figure 4.36) is developed for treating chronic hepatitis C infection. It is recommended as an addition to the current standard regimen of PEG-interferon and ribavirin in treating patients infected with hepatitis C virus (HCV). Boceprevir is a peptidomimetic protease inhibitor with four moieties, P1-P3 and a Cap, where PI is a racemic p-aminoamide, P2 is a chiral dimethylcyclopropylproline analog, P3 is (S)-f rf-leucine, and Cap is a fcrf-butylcarbamoyl group [162,163]. 

Rupintrivir (72, Scheme 2.11) is a peptidomimetic protease inhibitor developed by Agouron Pharmaceuticals (San Diego, CA) for the treatment of human rhinovirus (HRV). A key component of the rupintrivir pharmacophore is the a,(3-unsaturated ester moiety, which acts as a Michael acceptor, forming a covalent bond with cysteine residues in the active site of HRV 3C protease. Synthesis of the 7-amino a,(3-unsaturated ester portion of rupintrivir involved coupling L-glutamic acid derivative 66 with 4-benzyloxazolidinone 67 via a mixed anhydride. Formation of the corresponding sodium enolate, followed by alkylation with allyl iodide 69, gave the a-allyl amide 70. 

Zhang, Y., Hsieh, Y., Izumi, T., Lin, E. T., Benet, L. Z., EfFects of ketoconazole on the intestinal metabolism, transport and oral bioavailability of K02, a novel vinylsulfone peptidomimetic cysteine protease inhibitor and a P450 3A, P-glycoprotein dual substrate, in male Sprague-Dawley rats, J. Pharmacol. 

W. Potts, R. van Horn, K. Anderson, T. Blake, E. Garver, G. Joseph, G. Dreyer, A. Shu, R. Heys, K. L. Fong, Characterization of the Metabolites of the Peptidomimetic Human Immunodeficiency Virus Type 1 Protease Inhibitor SK F 107461 in Rats Using Liquid Chromatography/Mass Spectrometry , Drug Metab. Dispos. 1995, 23, 799 - 805. 

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... 

Peptidomimetics in which one amide bond is replaced by a phosphinic acid (R-P(0H)(=0)-R phosphinic peptides ) are of interest as potential protease inhibitors [17-19]. These compounds have been prepared either from orthogonally protected phosphorus-containing monomers [17,18,20], or by forming the phosphorus-containing fragments on solid phase, as sketched in Figure 11.4 [19,21], Phosphinic acids have been prepared on solid phase mainly by reaction of carbon electrophiles with monoalkylphosphinates. As carbon electrophiles, acrylates, aldehydes, reactive alkyl halides, or a, 3-unsaturated ketones can be used. 

Indinavir is a peptidomimetic hydroxy ethylene protease inhibitor that is ten times more potent against HIV-1 enzyme than HIV-2. Following the binding of indinavir to the viral protease, the protease is no longer able to process the gag-pol polyprotein precursors, resulting in the production of immature HIV particles that lack the... 

The penicillin antibiotics inhibit transpeptidase enzymes (penicillin-binding proteins (PBPs)) by acylation of the serinyl residue at their active site, which leads to cell wall lysis, since blocking PBPs circumvents proper murein membrane formation [3]. Several peptides and peptidomimetics containing the (3-lactam ring have been recently described as effective protease inhibitors and, consequently, as potential drugs for a wide range of diseases implicating proteases [5-8]. 

HIV protease hydrolyzes multiprotein peptides, and the leads for HIV protease inhibitors were polypeptides. It is natural that HIV protease inhibitors still bear a resemblance to a polypeptide. Successful development of Pis required liberal use of peptidomimetic strategies to create orally available drugs. 

CGP 57813 is a peptidomimetic inhibitor of human HIV-1 protease. This lipophilic compound has been successfully entrapped in polylactic acid (PLA) and into pH-sensitive methacrylic acid copolymer particles (EUDRAGIT L 1 GO-55) [69], After the application of a film-coating, the plasma concentration was acceptable and reached similar levels as with injections of drug-loaded PLA carriers. To hinder the proteolytic degradation of a drug, two types of enteric-coated pellets were applied simultaneously. One contained the protease inhibitor coated... 

Phosphonopeptides containing a transition state analog of the hydrolysis of the amide bond represent another attractive approach for the preparation of proteolitically stable peptides (10,30,31). In addition to increased stability, incorporation of a phosphonate moiety into the peptide sequence provides access to additional binding interactions within the transition-state conformation of the enzyme/substrate complex (13). This peptidomimetic approach is used to design very effective protease inhibitors (31-34). As in the case... 

Zhang Y, Benet LZ. Characterization of P-glycoprotein mediated transport of K02, a novel vinylsulfone peptidomimetic cysteine protease inhibitor, across MDR1-MDCK and Caco-2 cell monolayers. Pharm Res 1998 15(10) 1520-1524. 

Tossi A, Bonin I, Antcheva N, Norbedo S, Benedetti F, Miertus S, Nair AC, Maliar T, Dal Bello F, Palu G, Romeo D, Aspartic protease inhibitors—An integrated approach for the design and synthesis of diaminodiol-based peptidomimetics, Eur. J. Biochem., 267 1715-1722, 2000. 

Figure 1.16 Left Schematic presentation of the 1,3-diaminopropanone core moiety as cysteine protease-directed and active site-spanning inhibitor principle (top). Upon reaction with the enzyme nucleophile, the ketone is reversibly converted to a hemithioketal (bottom). Right Peptidomimetic cysteine protease inhibitors of subsequent generations are depicted together with their inhibitory activity and primary targets.

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