Pyrrolidine-5,5-trans-lactams. 4. Incorporation of a P3/P4 urea leads to potent intracellular inhibitors of hepatitis C virus NS3/4A protease.
[reaction: see text] In this, the first of two Letters, we describe how a P3/P4 urea linking unit was used to greatly enhance the biochemical and replicon potency of inhibitors based upon the pyrrolidine-5,5-trans-lactam template. Compound 7b demonstrated a 100 nM IC(50) in the replicon cell-based surrogate HCV assay.
Slater
Martin J
MJ
GlaxoSmithKline Medicines Research Center, Gunnels Wood Road, Stevenage, SG1 2NY, UK. martin.j.slater@gsk.com
Amphlett
Elizabeth M
EM
Andrews
David M
DM
Bamborough
Paul
P
Carey
Seb J
SJ
Johnson
Martin R
MR
Jones
Paul S
PS
Mills
Gail
G
Parry
Nigel R
NR
Somers
Donald O'N
DO
Stewart
Alan J
AJ
Skarzynski
Tadeusz
T
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D020128:Inhibitory Concentration 50; D007769:Lactams / Q000737:chemistry*; D008968:Molecular Conformation; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011759:Pyrrolidines / Q000737:chemistry*; D014508:Urea / Q000737:chemistry*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D007769:Lactams; D011480:Protease Inhibitors; D011759:Pyrrolidines; D014508:Urea; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C032519:pyrrolidine