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.
Department of Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, SG1 2NY, Stevenage, UK. david.m.andrews@gsk.com
David M
DM
Andrews
Helene M
HM
Chaignot
Barry A
BA
Coomber
Mike D
MD
Dowle
S Lucy
SL
Hind
Martin R
MR
Johnson
Paul S
PS
Jones
Gail
G
Mills
Angela
A
Patikis
Tony J
TJ
Pateman
J Ed
JE
Robinson
Martin J
MJ
Slater
Naimisha
N
Trivedi
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