title: Pyrrolidine-5,5-trans-lactams. 5. Pharmacokinetic optimization of inhibitors of hepatitis C virus NS3/4A protease.
abstract: [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.
authors: GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, UK. david.andrews@astrazeneca.com
authors: David M
authors: DM
authors: Andrews
authors: Michael C
authors: MC
authors: Barnes
authors: Mike D
authors: MD
authors: Dowle
authors: S Lucy
authors: SL
authors: Hind
authors: Martin R
authors: MR
authors: Johnson
authors: Paul S
authors: PS
authors: Jones
authors: Gail
authors: G
authors: Mills
authors: Angela
authors: A
authors: Patikis
authors: Tony J
authors: TJ
authors: Pateman
authors: Tracy J
authors: TJ
authors: Redfern
authors: J Ed
authors: JE
authors: Robinson
authors: Martin J
authors: MJ
authors: Slater
authors: Naimisha
authors: N
authors: Trivedi
mesh_terms: 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
chemical_list: 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