Identification of [(naphthalene-1-carbonyl)-amino]-acetic acid derivatives as nonnucleoside inhibitors of HCV NS5B RNA dependent RNA polymerase

Ariamala Gopalsamy; Kitae Lim; John W Ellingboe; Girija Krishnamurthy; Mark Orlowski; Boris Feld; Marja van Zeijl; Anita Y M Howe

doi:10.1016/j.bmcl.2004.06.013

Identification of [(naphthalene-1-carbonyl)-amino]-acetic acid derivatives as nonnucleoside inhibitors of HCV NS5B RNA dependent RNA polymerase

Bioorg Med Chem Lett. 2004 Aug 16;14(16):4221-4. doi: 10.1016/j.bmcl.2004.06.013.

Authors

Ariamala Gopalsamy¹, Kitae Lim, John W Ellingboe, Girija Krishnamurthy, Mark Orlowski, Boris Feld, Marja van Zeijl, Anita Y M Howe

Affiliation

¹ Chemical and Screening Sciences, Wyeth Research, 401 N Middletown Road, Pearl River, NY 10965, USA. [email protected]

PMID: 15261274
DOI: 10.1016/j.bmcl.2004.06.013

Abstract

A novel series of HCV NS5B RNA dependent RNA polymerase inhibitors containing a naphthalene carboxamide scaffold were identified by high throughput screening. Optimization of substituents by parallel synthesis and the iterative design towards understanding structure-activity relationship to improve potency are described. Tetra substituted naphthalene 31 displayed potent activity with IC(50) of 120 nM against HCV NS5B enzyme and was selective over a panel of polymerases.

MeSH terms

Acetates / chemistry*
Acetates / pharmacology*
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology
RNA-Dependent RNA Polymerase / antagonists & inhibitors*
Structure-Activity Relationship
Viral Nonstructural Proteins / antagonists & inhibitors*

Substances

Acetates
Enzyme Inhibitors
Viral Nonstructural Proteins
NS-5 protein, hepatitis C virus
RNA-Dependent RNA Polymerase