Design and synthesis of ethyl pyrrolidine-5,5-trans-lactams as inhibitors of hepatitis C virus NS3/4A protease.
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.
Slater
Martin J
MJ
GlaxoSmithKline Medicines Research Centre, Stevenage, UK. mjs40312@gsk.com
Andrews
David M
DM
Baker
Graham
G
Bethell
Susanne S
SS
Carey
Seb
S
Chaignot
Helene
H
Clarke
Berwyn
B
Coomber
Barry
B
Ellis
Malcolm
M
Good
Andrew
A
Gray
Norman
N
Hardy
George
G
Jones
Paul
P
Mills
Gail
G
Robinson
Ed
E
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
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