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Abstract: A novel series of non-nucleoside small molecules containing a tricyclic dihydropyridinone structural motif was identified as potent HCV NS5B polymerase inhibitors. Driven by structure-based design and building on our previous efforts in related series of molecules, we undertook extensive SAR studies, in which we identified a number of metabolically stable and very potent compounds in genotype 1a and 1b replicon assays. This work culminated in the discovery of several inhibitors, which combined potent in vitro antiviral activity against both 1a and 1b genotypes, metabolic stability, good oral bioavailability, and high C 12 (PO)/EC50 ratios. [Copyright &y& Elsevier]

Abstract: The discovery of 5,5′- and 6,6′-dialkyl-5,6-dihydro-1H-pyridin-2-ones as potent inhibitors of the HCV RNA-dependent RNA polymerase (NS5B) is described. Several of these agents also display potent antiviral activity in cell culture experiments (EC50 <0.10μM). In vitro DMPK data for selected compounds as well as crystal structures of representative inhibitors complexed with the NS5B protein are also disclosed. [Copyright &y& Elsevier]

Abstract: 5,6-Dihydro-1H-pyridin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Among these, compound 4ad displayed potent inhibitory activities in biochemical and replicon assays (IC50 (1b)<10nM; IC50 (1a)<25nM, EC50 (1b)=16nM), good in vitro DMPK properties, as well as moderate oral bioavailability in monkeys (F =24%). [Copyright &y& Elsevier]

Abstract: Hexahydro-pyrrolo- and hexahydro-1H-pyrido[1,2-b]pyridazin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Among these, compound 4c displayed potent inhibitory activities in biochemical and replicon assays (IC50 (1b) <10nM; EC50 (1b)=34nM) as well as good stability towards human liver microsomes (HLM t 1/2 =59min). [Copyright &y& Elsevier]

Abstract: 4-(1,1-Dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-5-hydroxy-2H-pyridazin-3-one analogs were discovered as a novel class of inhibitors of HCV NS5B polymerase. Structure-based design led to the identification of compound 3a that displayed potent inhibitory activities in biochemical and replicon assays (1b IC50 <10 nM; 1b EC50 =1.1nM) as well as good stability toward human liver microsomes (HLM t 1/2 >60min). [Copyright &y& Elsevier]

Abstract: Pyrrolo[1,2-b]pyridazin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Structure-based design led to the discovery of compound 3k, which displayed potent inhibitory activities in biochemical and replicon assays (IC50 (1b)<10nM; EC50 (1b)=12nM) as well as good stability towards human liver microsomes (HLM t 1/2 >60min). [Copyright &y& Elsevier]