Pyrrolidine-5,5-trans-lactams. 5. Pharmacokinetic optimization of inhibitors of hepatitis C virus NS3/4A protease.
[reaction: see text] In this, the second of two Letters, the optimization of the pyrrolidine-5,5-trans-lactam template (exemplified by 1a) as a mechanism-based inhibitor of hepatitis C NS3/4A protease is described. "Right Box" analysis of cassette dosing screening pharmacokinetic data was used to rapidly categorize the compounds. GW0014 (compound 4d) emerged as the compound displaying an optimal balance of biochemical and replicon potency, along with low i.v. clearance in the dog.
Andrews
David M
DM
GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, UK. david.andrews@astrazeneca.com
Barnes
Michael C
MC
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
Redfern
Tracy J
TJ
Robinson
J Ed
JE
Slater
Martin J
MJ
Trivedi
Naimisha
N
D020128:Inhibitory Concentration 50; D007769:Lactams / Q000737:chemistry*; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D011759:Pyrrolidines / Q000737:chemistry*; 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; C032519:pyrrolidine