The design of potent, non-peptidic inhibitors of hepatitis C protease.
The pyrrolidine-5,5-trans-lactam template was used to design small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease displaying potent activity in the replicon cell-based assay. The activity of this series is not dependent upon its chemical reactivity and molecules have been synthesised which combine enhanced biochemical potency with improved plasma stability. Promising initial pharmacokinetic data indicating the potential for further optimisation of this series into low molecular weight, drug-like inhibitors is presented.
Andrews
David M
DM
Department of Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, SG1 2NY, Stevenage, UK. david.m.andrews@gsk.com
Chaignot
Helene M
HM
Coomber
Barry A
BA
Dowle
Mike D
MD
Hind
S Lucy
SL
Johnson
Martin R
MR
Jones
Paul S
PS
Mills
Gail
G
Patikis
Angela
A
Pateman
Tony J
TJ
Robinson
J Ed
JE
Slater
Martin J
MJ
Trivedi
Naimisha
N
D000818:Animals; D018360:Crystallography, X-Ray; D004285:Dogs; D015195:Drug Design; D004355:Drug Stability; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007275:Injections, Intravenous; D007769:Lactams / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D008954:Models, Biological; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D007769:Lactams; D011480:Protease Inhibitors; D011759:Pyrrolidines; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases