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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Hepatitis C Virus NS3 Protease Inhibitors Based on a2(1H)-Pyrazinone-Glycine ScaffoldAnna Karin Belfrage 1 , Johan Gising 1 , Pernilla Örtqvist 1 ,Aparna Vema 1 , Sofia Svahn Gustafsson 2 , Mats Larhed 1 ,U. Helena Danielson 2 , and Anja Sandström 11 Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, UppsalaUniversity, Box 574, SE-751 23, Uppsala, Sweden; 2 Department of Biochemistry andOrganic Chemistry, BMC, Uppsala University, Box 596, SE-751 24, Uppsala, SwedenIntroductionHepatitis C virus (HCV) infection is a serious and growing threat to public health. Anestimated 170 million of the global population are infected and at risk of developingcirrhosis or cancer [1]. The current standard treatment, associated with severe adverseeffects, involves acombination of pegylatedinterferon-α and ribavirin.The efficacy is dependenton the genotype of the viruswith sustained virologicalFig. 1. Lead compounds A and B.response in only 40-50% ofgenotype 1 infected patients[2]. Viral resistance is oneof the major issues in future development of HCV therapies. To combat the mutated virusthere is a need for novel inhibitors based on structural motifs different from those of knownanti-HCV clinical candidates. Substituted pyrazinones can act asβ-strand inducers in protease inhibitors. Consequently, thisheterocyclic system is interesting from a medicinal chemistry point ofview. We have previously reported a rapid microwave method forsynthesis of N-1, C-6-disubstituted 3,5-dichloro-2-(1H)-pyrazinonesFig. 2. Proteaseinhibitors.[3] and its promising incorporation in small HCV NS3 proteaseinhibitors. We herein present our further optimization of these leadcompounds (A, B) (Figure 1) [4].Results and DiscussionMolecular modelling of HCV NS3 protease inhibitors, of the type shown in Figure 2,suggested that the space occupied by the P2 side chain could be reached by the substituentin position six on the P3-pyrazinone [4]. Based on these results we hypothesized that aScheme 1.232