Novel thiazolones as HCV NS5B polymerase allosteric inhibitors: Further designs, SAR, and X-ray complex structure

Shunqi Yan; Gary Larson; Jim Z Wu; Todd Appleby; Yili Ding; Robert Hamatake; Zhi Hong; Nanhua Yao

doi:10.1016/j.bmcl.2006.09.095

Novel thiazolones as HCV NS5B polymerase allosteric inhibitors: Further designs, SAR, and X-ray complex structure

Bioorg Med Chem Lett. 2007 Jan 1;17(1):63-7. doi: 10.1016/j.bmcl.2006.09.095. Epub 2006 Oct 4.

Authors

Shunqi Yan¹, Gary Larson, Jim Z Wu, Todd Appleby, Yili Ding, Robert Hamatake, Zhi Hong, Nanhua Yao

Affiliation

¹ Valeant Pharmaceuticals Research and Development, 3300 Hyland Ave., Costa Mesa, CA 92626, USA. [email protected]

PMID: 17049849
DOI: 10.1016/j.bmcl.2006.09.095

Abstract

Structure-activity relationships (SAR) of 1 against HCV NS5B polymerase were described. SAR explorations and further structure-based design led to the identifications of 2 and 3 as novel HCV NS5B inhibitors. X-ray structure of 3 in complex with NS5B polymerase was obtained at a resolution of 2.2A, and confirmed the design.

MeSH terms

Allosteric Regulation
Antiviral Agents / chemistry*
Antiviral Agents / pharmacology*
Crystallography, X-Ray
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Molecular Conformation
Protein Conformation
Structure-Activity Relationship
Thiazoles / chemistry*
Thiazoles / pharmacology*
Viral Nonstructural Proteins / antagonists & inhibitors*

Substances

Antiviral Agents
Enzyme Inhibitors
Thiazoles
Viral Nonstructural Proteins
NS-5 protein, hepatitis C virus