Stereoselective synthesis and biological evaluation as inhibitors of hepatitis C virus RNA polymerase of GSK3082 analogues with structural diversity at the 5-position

1区 · 医学

Article

作者: Olga Abian ; Adrian Velázquez-Campoy ; Juan J. Galano-Frutos ; Rafael Clavería-Gimeno ; María D. Díaz-de-Villegas ; Javier Sancho ; José A. Gálvez

GSK3082 - a hepatitis C virus RNA polymerase inhibitor - and a series of analogues with structural diversity at the 5-position were prepared from a 2,2,4,5-tetrasubstituted pyrrolidine obtained with a well-defined stereochemistry from the 1,3-dipolar cycloaddition of the chiral imino ester derived from leucine tert-butyl ester and (R)-2,3-O-isopropylideneglyceraldehyde with methyl acrylate. The chiral 2,2-dimethyl-1,3-dioxolane moiety provided by the glyceraldehyde served as a synthetic equivalent for different substituents and functional groups and these transformations usually required mild reaction conditions and simple work-up procedures. The inhibitory activity of the resulting GSK3082 analogues was studied in vitro in a cell-based assay of the subgenomic HCV RNA replication system. Some of the analogues showed good inhibitory activity with IC50 values in the nanomolar concentration range.

2008-04-01·The Journal of Organic Chemistry2区 · 化学

Asymmetric Synthesis of anN-Acylpyrrolidine for Inhibition of HCV Polymerase

2区 · 化学

Article

作者: Haigh, David ; Corfield, John A. ; Flanagan, Roy C. ; Howes, Peter D. ; Glover, Bobby N. ; Millar, Alan ; Guidetti, Rossella ; Xie, Shiping ; Matsuoka, Richard T. ; Sharp, Matthew J. ; Cooley, Bob E. ; Copley, Royston C. B. ; Toczko, Jennifer F. ; Agbodjan, Armel A. ; Jackson, Mary M. ; Medhurst, Katrina J. ; Slater, Martin J.

A practical asymmetric synthesis of a highly substituted N-acylpyrrolidine on multi-kilogram scale is described. The key step in the construction of the three stereocenters is a [3+2] cycloaddition of methyl acrylate and an imino ester prepared from l-leucine t-butyl ester hydrochloride and 2-thiazolecarboxaldehyde. The cycloaddition features novel asymmetric catalysis via a complex of silver acetate and a cinchona alkaloid, particularly hydroquinine, with complete diastereomeric control and up to 87% enantiomeric control. The alkaloid serves as a ligand as well as a base for the formation of the azomethine ylide or 1,3-dipole. Experiments have shown that the hydroxyl group of hydroquinine is a critical element for the enantioselectivities observed. The cycloaddition methodology is also applicable to methylvinyl ketone, providing access to either alpha- or beta-epimers of 4-acetylpyrrolidine depending on the reaction conditions utilized. The synthesis also highlights an efficient N-acylation, selective O- versus N-methylation, and a unique ester reduction with NaBH4-MeOH catalyzed by NaB(OAc)3H that not only achieves excellent chemoselectivity but also avoids formation of the undesired but thermodynamically favored epimer. The highly functionalized target is synthesized in seven linear steps from l-leucine t-butyl ester hydrochloride with all three isolated intermediates being highly crystalline.

2007-03-01·Journal of Medicinal Chemistry1区 · 医学

Optimization of Novel Acyl Pyrrolidine Inhibitors of Hepatitis C Virus RNA-Dependent RNA Polymerase Leading to a Development Candidate

1区 · 医学

Article

作者: Price, Helen ; Wonacott, Alan ; Jarvest, Richard L. ; Corfield, John A. ; Wilkinson, Claire ; Parry, Nigel R. ; Slater, Martin J. ; Fenwick, Rebecca H. ; Medhurst, Katrina J. ; Fernandes, Stephanie ; Burton, George ; Lovegrove, Victoria L. H. ; Bravi, Gianpaolo ; Hartley, C. David ; Amphlett, Elizabeth M. ; Howes, Peter D. ; Thommes, Pia ; Ellis, Malcolm R. ; Stocker, Richard ; Cheasty, Anne G. ; Jackson, Deborah L. ; Guidetti, Rossella ; Shah, Pritom ; Singh, Onkar M. P. ; Haigh, David ; Andrews, David M.

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.

100 项与 GSK3082 相关的药物交易

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