HCV NS3 protease inhibitor

Scheme 22 Synthesis of an HCV NS3 protease inhibitor via a microwave-induced amido-carbonylation reaction...

Figure 8.16 Cyclization of an HCV NS3 protease inhibitor. (Chen, K.X., et al. Novel potent hepatitis C virus NS3 protease inhibitors derived from proline-based macrocycles. J. Med. Chem. 2006, 49, 995-1005.)...

Chen, K. X. Njoroge, F. G. Discovery of Boceprevir and Narlaprevir The First and Second Generation of HCV NS3 Protease Inhibitors. In Case Studies in Modern Drug Discovery and Development, Huang, X. Aslanian, R. G., Eds. Wiley Hoboken, NJ, USA, 2012 pp. 296-335. 

Many protease/peptidase inhibitor peptidomimetics include a-ketoamide moieties as key bioactive functionalities and the Passerini reaction provides a facile entry for their preparation through the oxidation of a-hydroxy amides. Researchers at Schering-Plough have utilized this strategy to synthesize a variety of a macrocyclic a-ketoamides towards the development of Hepatitis C virus (HCV) NS3 protease inhibitors. Aldehyde 56 was treated with allylisocyanide and acetic acid to give a-acyloxyamide... 

Sing WT, Lee CL, Yeo SL, Lim SP, Sim MM (2001) Arylalfcylidene rhodanine with bulky and hydrophobic functional group as selective HCV NS3 protease inhibitor. Bioorg Med Chem Lett 11 91 94... 

An interesting application of tiie nitro-catalyst 6 has been recently published by Boehringer IngeUieim Ltd. in synthesis of BILN 2061 (Ciluprevir), the first reported hepatitis C virus (HCV) NS3 protease inhibitor to have shown... 

Of the currently available HIV medications, seven are HTV protease inhibitors. Similar to the above-mentioned HCV NS3 protease inhibitors, the described inhibitors are quite large and have a peptide-like appearance. Often, they have to be synthesized in sequence with up to 20 synthesis steps. Therefore, it is worthwhile considering alternative synthetic approaches involving MCRs. For example, the key intermediate piperazine 49 of Crixivan (Indinavir) produced by Merck was advantageously and stereoselectively synthesized using a key and quantitative U-4CR followed by an enantioselective hydrogenation [28]. 

The presented protocol was applied to the synthesis of a building block in the synthetic route to an HCV NS3 protease inhibitor (Scheme 4.8). Gratifyingly, no racemization of the norvahne a-carbon occurred in the carbonylation step as only one diastereomer of the inhibitor was detected [22]. 

The RCM macrocyclization has been successfully applied to the synthesis of antiviral agent BILN 2061 (Cilu-previr, 32), a hepatitis C virus (HCV) NS3 protease inhibitor (Scheme 24.10)." The key step of the synthesis is the RCM of the diene 30 using first-generation Hoveyda catalyst [Ru]-V, leading to the cyclic 15-membered olefinic compound 31 exclusively as a Z-isomer in good yield. In the reaction, a side product generated from intermolecular... 

Poirier M, Simoneau, B. Tsantrizos, YS, Llinas-Brunet, M. Synthesis of BILN 2061, an HCV NS3 protease inhibitor with proven antiviral effect in humans. Org. Lett. 2004 6 2901 2904. 

The synthesis of l-amino-2-vinylcyclopropane-l-phosphonic add diethyl ester (534) and its resolution have been reported by Pyun and co-workers. The enantiomerically pure material has been used to synthesize an extremely potent tripeptide phosphonate inhibitor of HCV NS3 protease (535). ... 

Compounds 23 (R = alkyl, aryl), 29 and 29 exhibited a high inhibitor activity against HCV NS3 protease. Their IC50 values against the full length of HCV-NS3/ 4A protease activity ranged between 6 and 86 nM for compounds 23 and between 3 and 11 nM for compounds 29 and 29. Their EC50 values for HCV replication in... 

In a more recent example of the application of isosterism, we have pioneered the use of the cyclopropyl acylsulfonamide moiety as a carboxylic acid isostere in the context of inhibitors of HCV NS3 protease [7, 8]. This moiety confers a significant increase in potency, 50-fold in the matched pair of inhibitors 6 and 7, and has been widely adopted by the industry as a design element [9]. 

As medicinal chemistry teams began to design and synthesize new NS3 protease inhibitors, a preliminary assessment of inhibitor potency was accomplished using a functional biochemical enzyme assay. The eventual development of a cell-based HCV replicon assay enabled the assessment of new inhibitors in a more physiologically cellular environment, thus providing a major advance in discovery efforts for this target. 

X-ray crystal structures of the HCV NS3 protease have been determined and have provided a wealth of information on inhibitor binding and... 

Figure 7.10a Modeling of a hypothetical benzoxaborole inhibitor derived from danoprevir with HCV NS3 protease. Potential polar interactions for PI -benzoxaborole include main chain and side chain of Thr 42, and...

Lin K, Pemi RB, Kwong AD, Lin C (2006) VX-950, a novel hepatitis C vims (HCV) NS3 A protease inhibitor, exhibits potent antiviral activities in HCV repUcon cells. Antimicrob Agents Chemother 50 1813-1822... 

Tai CL, Chi WK, Chen DS, Hwang LH (1996) The helicase activity associated with hepatitis C virus nonstructural protein 3 (NS3). J Virol 70 8477-8484 Tong X, Chase R, Skelton A, Chen T, Wright-Minogue J, Malcolm BA (2006) Identification and analysis of fitness of resistance mutations against the HCV protease inhibitor SCH 503034. Antiviral Res 70 28-38... 

---