Discovery of benzophosphadiazine drug candidate IDX375: A novel hepatitis C allosteric NS5B RdRp inhibitor. Issue 11 (1st June 2017)

• Record Type: Journal Article
• 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.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 11(2017)
• Page Start: 2634
• Page End: 2640
• Publication Date: 2017-06-01
• Subjects: Hepatitis C virus -- Direct-acting antivirals -- NS5B non-nucleoside inhibitors -- Allosteric inhibitors -- Phosphadiazines -- Phophorylated bioisosteres -- Thiadiazine bioisosteres -- IDX375; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.01.017
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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.