Synthesis of potent and broad genotypically active NS5B HCV non-nucleoside inhibitors binding to the thumb domain allosteric site 2 of the viral polymerase

• Published in: Bioorganic & medicinal chemistry letters Vol. 26; no. 18; pp. 4536 - 4541
• Main Authors: Pierra Rouvière, Claire, Amador, Agnès, Badaroux, Eric, Convard, Thierry, Da Costa, Daniel, Dukhan, David, Griffe, Ludovic, Griffon, Jean-François, LaColla, Massimiliano, Leroy, Frédéric, Liuzzi, Michel, Loi, Anna Giulia, McCarville, Joe, Mascia, Valeria, Milhau, Julien, Onidi, Loredana, Paparin, Jean-Laurent, Rahali, Rachid, Sais, Efisio, Seifer, Maria, Surleraux, Dominique, Standring, David, Dousson, Cyril
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15-09-2016
• Subjects: Allosteric inhibitors; Allosteric Site; Amide bioisostere; Antiviral Agents - chemistry; Antiviral Agents - metabolism; Antiviral Agents - pharmacology; Crystallography, X-Ray; Direct-acting antivirals; Genotype; Hepacivirus - drug effects; Hepatitis C virus; NS5B non-nucleoside inhibitors; Polymerase inhibitors; Structure-Activity Relationship; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - metabolism; Amide bioisostere; Polymerase inhibitors; Allosteric inhibitors; NS5B non-nucleoside inhibitors; Hepatitis C virus; Direct-acting antivirals
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.01.042

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The 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 Letter describes the discovery of a new family of HCV NS5B non-nucleoside inhibitors, based on the bioisosterism between amide and phosphonamidate functions. As part of this program, SAR in this new series led to the identification of IDX17119, a potent non-nucleoside inhibitor, active on the genotypes 1b, 2a, 3a and 4a. The structure and binding domain of IDX17119 were confirmed by X-ray co-crystallization study.