The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.

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MNDO calculations for [3]-, [4]-, and [5]-pericyclyne indicate that interactions between triple bonds are hyperconjugative in the n system and homoconjugative in the o system and that [3]pericyclyne may be interconverted with a valence tautomer, tricyclopropabenzene.Recently, Scott et al. reported1 the synthesis and photoelectron spectrum of decamethyl[5]pericyclyne ( l ) , the permethylated derivative of (2). A number of low energy ionizations were observed, implying interactions between the 7c MOs of the acetylene groups. These interactions were assumed to be of the homoconjugative (through-space) type and similar

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