Pyrrolidine-5,5-trans-lactams. 5. Pharmacokinetic Optimization of Inhibitors of Hepatitis C Virus NS3/4A Protease

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...

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Bibliographic Details
Published in:Organic letters 2003-11, Vol.5 (24), p.4631-4634
Main Authors: Andrews, David M, Barnes, Michael C, Dowle, Mike D, Hind, S. Lucy, Johnson, Martin R, Jones, Paul S, Mills, Gail, Patikis, Angela, Pateman, Tony J, Redfern, Tracy J, Robinson, J. Ed, Slater, Martin J, Trivedi, Naimisha
Format: Article
Language:English
Subjects:
Inhibitory Concentration 50
Lactams - chemistry
Molecular Structure
Protease Inhibitors - chemical synthesis
Protease Inhibitors - chemistry
Protease Inhibitors - pharmacokinetics
Pyrrolidines - chemistry
Viral Nonstructural Proteins - antagonists & inhibitors
Viral Nonstructural Proteins - metabolism
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Summary: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.
ISSN:1523-7060
1523-7052
DOI:10.1021/ol035827n