Hexahydro-pyrrolo- and hexahydro-1H-pyrido[1,2-b]pyridazin-2-ones as potent inhibitors of HCV NS5B polymerase

Frank Ruebsam; Zhongxiang Sun; Benjamin K Ayida; Stephen E Webber; Yuefen Zhou; Qiang Zhao; Charles R Kissinger; Richard E Showalter; Amit M Shah; Mei Tsan; Rupal Patel; Laurie A Lebrun; Ruhi Kamran; Maria V Sergeeva; Darian M Bartkowski; Thomas G Nolan; Daniel A Norris; Leo Kirkovsky

doi:10.1016/j.bmcl.2008.08.017

Hexahydro-pyrrolo- and hexahydro-1H-pyrido[1,2-b]pyridazin-2-ones as potent inhibitors of HCV NS5B polymerase

Bioorg Med Chem Lett. 2008 Sep 15;18(18):5002-5. doi: 10.1016/j.bmcl.2008.08.017. Epub 2008 Aug 9.

Authors

Frank Ruebsam¹, Zhongxiang Sun, Benjamin K Ayida, Stephen E Webber, Yuefen Zhou, Qiang Zhao, Charles R Kissinger, Richard E Showalter, Amit M Shah, Mei Tsan, Rupal Patel, Laurie A Lebrun, Ruhi Kamran, Maria V Sergeeva, Darian M Bartkowski, Thomas G Nolan, Daniel A Norris, Leo Kirkovsky

Affiliation

¹ Anadys Pharmaceuticals, Inc., 3115 Merryfield Row, San Diego, CA 92121, USA. [email protected]

PMID: 18722768
DOI: 10.1016/j.bmcl.2008.08.017

Abstract

Hexahydro-pyrrolo- and hexahydro-1H-pyrido[1,2-b]pyridazin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Among these, compound 4c displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b) <10 nM; EC(50) (1b)=34 nM) as well as good stability towards human liver microsomes (HLM t(1/2) =59 min).

MeSH terms

Antiviral Agents / chemical synthesis*
Antiviral Agents / chemistry
Antiviral Agents / pharmacology*
Combinatorial Chemistry Techniques
Crystallography, X-Ray
Drug Design
Hepacivirus / drug effects*
Humans
Microsomes, Liver / drug effects*
Molecular Structure
Pyridazines / chemical synthesis*
Pyridazines / chemistry
Pyridazines / pharmacology*
Structure-Activity Relationship
Viral Nonstructural Proteins / antagonists & inhibitors*

Substances

Antiviral Agents
Pyridazines
Viral Nonstructural Proteins
NS-5 protein, hepatitis C virus