Optimization of novel acyl pyrrolidine inhibitors of hepatitis C virus RNA-dependent RNA polymerase leading to a development candidate.
Optimization of a pyrrolidine-based template using structure-based design and physicochemical considerations has provided a development candidate 20b (3082) with submicromolar potency in the HCV replicon and good pharmacokinetic properties.
Slater
Martin J
MJ
Infectious Diseases CEDD and Medicinal Discovery Research, GlaxoSmithKline, GSK Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom. martin.j.slater@gsk.com
Amphlett
Elizabeth M
EM
Andrews
David M
DM
Bravi
Gianpaolo
G
Burton
George
G
Cheasty
Anne G
AG
Corfield
John A
JA
Ellis
Malcolm R
MR
Fenwick
Rebecca H
RH
Fernandes
Stephanie
S
Guidetti
Rossella
R
Haigh
David
D
Hartley
C David
CD
Howes
Peter D
PD
Jackson
Deborah L
DL
Jarvest
Richard L
RL
Lovegrove
Victoria L H
VL
Medhurst
Katrina J
KJ
Parry
Nigel R
NR
Price
Helen
H
Shah
Pritom
P
Singh
Onkar M P
OM
Stocker
Richard
R
Thommes
Pia
P
Wilkinson
Claire
C
Wonacott
Alan
A
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001682:Biological Availability; D002522:Chlorocebus aethiops; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D008958:Models, Molecular; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014709:Vero Cells
D000998:Antiviral Agents; D011759:Pyrrolidines; D012324:RNA-Dependent RNA Polymerase