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  • Title: Pyrrolidine-5,5-trans-lactams. 1. Synthesis and incorporation into inhibitors of hepatitis C virus NS3/4A protease.
    Author: Andrews DM, Carey SJ, Chaignot H, Coomber BA, Gray NM, Hind SL, Jones PS, Mills G, Robinson JE, Slater MJ.
    Journal: Org Lett; 2002 Dec 12; 4(25):4475-8. PubMed ID: 12465916.
    Abstract:
    [reaction: see text] In this, the first of two letters, we outline the use of the pyrrolidine-5,5-trans-lactam template to design small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease. The hitherto unreported reaction of the acyl iminium ion precursor 4 with dialkyl-substituted silyl ketene acetals (e.g., 8b) is described. Compound 12b, with a spirocyclobutyl P1 substituent and a cyclopropylacyl substituent on the lactam nitrogen, has a k(obs)/I of 400 M(-)(1) s(-)(1) and demonstrates activity in a replicon cell-based surrogate HCV assay.
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