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

Autor: Paparin JL; Idenix SARL, an MSD Company, Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsière, BP50001, 34189 Montpellier Cedex 4, France. Electronic address: jean-laurent.paparin@merck.com., Amador A; Former Idenix employee., Badaroux E; Former Idenix employee., Bot S; Idenix SARL, an MSD Company, Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsière, BP50001, 34189 Montpellier Cedex 4, France., Caillet C; Former Idenix employee., Convard T; Idenix SARL, an MSD Company, Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsière, BP50001, 34189 Montpellier Cedex 4, France., Da Costa D; Idenix SARL, an MSD Company, Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsière, BP50001, 34189 Montpellier Cedex 4, France., Dukhan D; Idenix SARL, an MSD Company, Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsière, BP50001, 34189 Montpellier Cedex 4, France., Griffe L; Former Idenix employee., Griffon JF; Idenix SARL, an MSD Company, Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsière, BP50001, 34189 Montpellier Cedex 4, France., LaColla M; Former Idenix employee., Leroy F; Former Idenix employee., Liuzzi M; Former Idenix employee., Giulia Loi A; Former Idenix employee., McCarville J; Former Idenix employee., Mascia V; Former Idenix employee., Milhau J; Idenix SARL, an MSD Company, Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsière, BP50001, 34189 Montpellier Cedex 4, France., Onidi L; Former Idenix employee., Pierra C; Idenix SARL, an MSD Company, Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsière, BP50001, 34189 Montpellier Cedex 4, France., Rahali R; Idenix SARL, an MSD Company, Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsière, BP50001, 34189 Montpellier Cedex 4, France., Rosinosky E; Former Idenix employee., Sais E; Former Idenix employee., Seifer M; Former Idenix employee., Surleraux D; Former Idenix employee., Standring D; Former Idenix employee., Dousson CB; Idenix SARL, an MSD Company, Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsière, BP50001, 34189 Montpellier Cedex 4, France.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2017 Jun 01; Vol. 27 (11), pp. 2634-2640. Date of Electronic Publication: 2017 Jan 13.
DOI: 10.1016/j.bmcl.2017.01.017
Abstrakt: 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.
(Copyright © 2017 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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