Discovery of benzophosphadiazine drug candidate IDX375: A novel hepatitis C allosteric NS5B RdRp inhibitor

[Display omitted] Hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells, and as a consequence is an attractive target for selective inhibition. This paper describes the discovery of a novel fam...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry letters Vol. 27; no. 11; pp. 2634 - 2640
Main Authors:	Paparin, Jean-Laurent, Amador, Agnès, Badaroux, Eric, Bot, Stéphanie, Caillet, Catherine, Convard, Thierry, Da Costa, Daniel, Dukhan, David, Griffe, Ludovic, Griffon, Jean-François, LaColla, Massimiliano, Leroy, Frédéric, Liuzzi, Michel, Giulia Loi, Anna, McCarville, Joe, Mascia, Valeria, Milhau, Julien, Onidi, Loredana, Pierra, Claire, Rahali, Rachid, Rosinosky, Elodie, Sais, Efisio, Seifer, Maria, Surleraux, Dominique, Standring, David, Dousson, Cyril B.
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01-06-2017
Subjects:	Allosteric inhibitors Allosteric Regulation Animals Antiviral Agents - chemical synthesis Antiviral Agents - chemistry Antiviral Agents - metabolism Antiviral Agents - pharmacology Binding Sites Crystallography, X-Ray Direct-acting antivirals Genotype Half-Life Haplorhini Hepacivirus - enzymology Hepacivirus - genetics Hepacivirus - physiology Hepatitis C virus Humans IDX375 Lactams - chemistry Lactams - pharmacology Mice Molecular Dynamics Simulation NS5B non-nucleoside inhibitors Organophosphorus Compounds - chemistry Organophosphorus Compounds - pharmacology Phophorylated bioisosteres Phosphadiazines Protein Structure, Tertiary Rats Structure-Activity Relationship Sulfonamides - chemistry Thiadiazine bioisosteres Viral Nonstructural Proteins - antagonists & inhibitors Viral Nonstructural Proteins - metabolism Virus Replication - drug effects Phosphadiazines NS5B non-nucleoside inhibitors Phophorylated bioisosteres Thiadiazine bioisosteres Allosteric inhibitors Hepatitis C virus IDX375 Direct-acting antivirals
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Summary:	[Display omitted] Hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells, and as a consequence is an attractive target for selective inhibition. This paper describes the discovery of a novel family of HCV NS5B non-nucleoside inhibitors inspired by the bioisosterism between sulfonamide and phosphonamide. Systematic structural optimization in this new series led to the identification of IDX375, a potent non-nucleoside inhibitor that is selective for genotypes 1a and 1b. The structure and binding domain of IDX375 were confirmed by X-ray co-crystalisation study.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2017.01.017