title: Design and synthesis of ethyl pyrrolidine-5,5-trans-lactams as inhibitors of hepatitis C virus NS3/4A protease.
abstract: Using a pyrrolidine-5,5-trans-lactam template, we have designed small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease. Compound 11a, with an alpha-ethyl P1 substituent and a Boc-valine substituent at the pyrrolidine nitrogen, has an IC(50)=30 microM.
authors.affiliation: GlaxoSmithKline Medicines Research Centre, Stevenage, UK. mjs40312@gsk.com
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Slater
authors.forename: David M
authors.initials: DM
authors.lastname: Andrews
authors.forename: Graham
authors.initials: G
authors.lastname: Baker
authors.forename: Susanne S
authors.initials: SS
authors.lastname: Bethell
authors.forename: Seb
authors.initials: S
authors.lastname: Carey
authors.forename: Helene
authors.initials: H
authors.lastname: Chaignot
authors.forename: Berwyn
authors.initials: B
authors.lastname: Clarke
authors.forename: Barry
authors.initials: B
authors.lastname: Coomber
authors.forename: Malcolm
authors.initials: M
authors.lastname: Ellis
authors.forename: Andrew
authors.initials: A
authors.lastname: Good
authors.forename: Norman
authors.initials: N
authors.lastname: Gray
authors.forename: George
authors.initials: G
authors.lastname: Hardy
authors.forename: Paul
authors.initials: P
authors.lastname: Jones
authors.forename: Gail
authors.initials: G
authors.lastname: Mills
authors.forename: Ed
authors.initials: E
authors.lastname: Robinson
mesh_terms: D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins; D007769:Lactams / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007769:Lactams; D011759:Pyrrolidines; D015842:Serine Proteinase Inhibitors; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus