Protease inhibitors development

Abstract This review provides an overview of the development of viral protease inhibitors as antiviral drugs. We concentrate on HlV-1 protease inhibitors, as these have made the most significant advances in the recent past. Thus, we discuss the biochemistry of HlV-1 protease, inhibitor development, clinical use of inhibitors, and evolution of resistance. Since many different viruses encode essential proteases, it is possible to envision the development of a potent protease inhibitor for other viruses if the processing site sequence and the catalytic mechanism are known. At this time, interest in developing inhibitors is Umited to viruses that cause chronic disease, viruses that have the potential to cause large-scale epidemics, or viruses that are sufQciently ubiquitous that treating an acute infection would be... 

A large scale synthesis of the drug Nelfi-navir, an HIV protease inhibitor developed by Agouron (now Pfizer) was reported with the amino alcohol derived from (148), prepared using the Jacobsen procedure described above (161). 

In a randomized comparison of a protease inhibitor-containing regimen and an efavirenz-containing regimen in 100 patients, six patients taking protease inhibitors developed nephrolithiasis one withdrew as a resnlt (12). 

In particular, the non-naturally occurring amino acid L-tert-leucine has received significant attention due to several pharmaceutically active compounds into which it is incorporated[1). HIV-protease inhibitors developed by Novartis and Abbott are based on L-tert-leudne 2, 3. Roche has developed the anti-arthritic compound Ro 31-9790 based on its potent inhibition of collagenase 41 and a key component in the synthesis of Ro 31-9790 is the methylamide of L-tert-leucine. Boehringer Ingelheim developed a series of compounds that inhibit the ribonucleotide redudase of Herpes... 

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. 

More than 50 endogenous and exogenous inhibitors of the calpains have been described as either transition-state reversible or irreversible inhibitors. The first transition-state inhibitors were the peptide aldehydes (e.g., leupeptin). Using this compound, new ones were synthesized that exhibited improved membrane permeability and calpain specificity (e.g., calpeptin). Other groups of inhibitors have since been discovered a-dicarbonyls (originally developed as serine protease inhibitors), nonpeptide quinolinecarboxamides,... 

Hurwitz SJ, Schinazi RF (2002) Development of a pharmacodynamic model for HIV treatment with nucleoside reverse transcriptase and protease inhibitors. Antiviral Res 56 115-127 Hurwitz SJ, Tennant BC, Korba BE, Gerin JL, Schinazi RF (1998) Pharmacodynamics of (—)-beta-2, 3 -dideoxy-3 -thiacytidine in chronically virus-infected woodchucks compared to its pharmacodynamics in humans, Antimicrob Agents Chemother 42 2804-2809 Hurwitz SJ, Otto MJ, Schinazi RF (2005) Comparative pharmacokinetics of Racivir, (+/-)-beta-2, 3 -dideoxy-5-fluoro-3 -thiacytidine in rats, rabbits, dogs, monkeys and HIV-infected humans, Antivir Chem Chemother 16 117-127... 

Currently, there is no approved antiviral therapy specifically targeting hepatitis C virus (HCV). The development of an HCV replicon system and our improved understanding of the structure and function of HCV proteins have led to the development of several classes of specific HCV inhibitors. NS3-4A protease inhibitors and NS5B polymerase inhibitors are furthest in development as discussed in Chaps. 2-4 (De and Migliaccio 2005 Manns et al. 2007 Pawlotsky et al. 2007). 

The development of resistance against HCV NS3/4 protease inhibitors will become a major challenge for the clinical use of these new compounds. Clinical trials of telaprevir (VX-950) have shown that mutations at different positions are rapidly selected (Sarrazin et al. 2005). In vitro studies indicate that cells bearing repUcons with those mutations are associated with different levels of resistance to telaprevir (< 10-fold change to >40-fold change in sensitivity). However, telaprevir-resistant mutants remain susceptible to interferon-a, at least in the replicon system. Likewise, replicon mutants that are resistant to boceprevir are still sensitive to interferon-a (Tong et al. 2006). 

HavUr DV, Richman DD (1996) Viral dynamics of HIV implications for drug development and therapeutic strategies. Ann Intern Med 124(11) 984—994 Hinrichsen H, Benhamou Y, Wedemeyer H, Reiser M, Sentjens RE, Calleja JL, Foms X, Erhardt A, Cronlein J, Chaves RL, Yong CL, Nehmiz G, Steinmann GG (2004) Short-term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype I patients. Gastroenterology 127(5) 1347-1355... 

Further, Wasserman and coworkers developed a direct acylation of stabilized phosphonium ylides by carboxylic acids in presence of the EDCI/DMAP (way c). This last method allows the introduction of a-aminoacid structures into the resulting P-oxo phosphorus ylides [19-25],opening the way to the total synthesis of depsipeptide elastase inhibitors [22,24] or cyclic peptidic protease inhibitor EurystatinA [20]. 

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