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Abstract: A tricyclic precursor for the synthesis of the prodrugs of pro-1,2,9,9a-tetrahydrocyclopropa[c]benz-[e]indole-4-one tetramethoxyindolecarboxamide (CBI-TMI) was prepared using the ring-closing metathesis approach. The tricyclic intermediate was converted to an advanced precursor of a CBI-TMI prodrug equipped with a linker presumably suitable for activation using the aldolase catalytic antibody 38C2. An attempted 38C2-catalyzed two-step activation of the hydroxy-pro-CBI intermediate involving retro-aldol and the β-elimination reactions was also examined. [Copyright &y& Elsevier]

Abstract: 5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as inhibitors of genotype 1 HCV NS5B polymerase. Lead optimization led to the discovery of compound 3a, which displayed potent inhibitory activities in biochemical and replicon assays [IC50 (1b)<10nM; IC50 (1a)=22nM; EC50 (1b)=5nM], good stability toward human liver microsomes (HLM t 1/2 >60min), and high ratios of liver to plasma concentrations 12h after a single oral administration to rats. [Copyright &y& Elsevier]

Abstract: 5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as inhibitors of genotype 1 HCV NS5B polymerase. The structure–activity relationship (SAR) associated with variation of the pyridazinone 2- and 6-substituents is discussed. The synthesis and metabolic stability of this new class of compounds are also described. [Copyright &y& Elsevier]

Abstract: We have developed two photolabile insulin prodrugs, insulin-2P and insulin-3P. These prodrugs were synthesized by protecting GlyA1 (NαA1), and one or both of the PheB1 (NαB1) and LysB29 (NεB29) amino groups in insulin using 5′-(α-methyl-nitro-piperonyl)oxy-carbonyl as the protecting group. These insulin prodrugs were efficiently activated by exposure to longwave UV light to produce insulin quantitatively. Using 2-deoxyglucose uptake assays, both di- and tri-protected compounds were less active than native insulin in the protected state, and showed comparable activity to native insulin upon photoactivation. [Copyright &y& Elsevier]

Through the introduction of a pyruvate segment by asymmetric propargylation and oxidation of terminal alkynes, both KDO and 4-epi-KDN have been concisely synthesized in the furanose form from readily available sugars in high overall yields. [Copyright &y& Elsevier]

α-Keto acid esters can be easily prepared in high yields in two steps from terminal alkynes via bromination and oxidation. This strategy provides a versatile access to the synthesis of biologically important natural products with an α-keto acid moiety. [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: 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: A 4-step synthesis of an optically active synthetic intermediate [(1R,2S)-2-(4′-fluorobenzylamino)cyclopentanecarboxylic acid ethyl ester complex with (S)-(+)-mandelic acid; compound 12, >99% de] required for the preparation of a promising HCV NS5B polymerase inhibitor is reported. This process utilizes mandelic acid as a resolving agent, which can be recovered in good yield by a simple extraction. An optimized version of the chemistry described avoids the use of chromatographic purifications making it suitable for large-scale applications. In addition, the straightforward conversion of compound 12 to enantiomerically pure (1R,2S)-2-aminocyclopentanecarboxylic acid ethyl ester and the corresponding Boc and Cbz derivatives is reported. The preparation of the enantiomer of 12 (compound 15) in enantiomerically pure form and the conversion of this entity to (1S,2R)-2-aminocyclopentanecarboxylic acid ethyl ester and the corresponding Boc and Cbz derivatives is also described. [Copyright &y& Elsevier]

Abstract: The synthesis of 4-(1′,1′-dioxo-1′,4′-dihydro-1′λ6-benzo[1′,2′,4′]thiadiazin-3′-yl)-5-hydroxy-2H-pyridazin-3-ones bearing 6-amino substituents 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 (microsome t 1/2, Caco-2 P app) for many of the compounds are also disclosed, and a crystal structure of a representative inhibitor complexed with the NS5B protein is discussed. [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]

Abstract: 5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as potent inhibitors of genotype 1 HCV NS5B polymerase focusing on the optimization of their drug metabolism and pharmacokinetics (DMPK) profiles. This investigation led to the discovery of potent inhibitors with improved DMPK properties. [Copyright &y& Elsevier]

Abstract: 5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as inhibitors of genotype 1 HCV NS5B polymerase. The synthesis, structure–activity relationships (SAR), metabolic stability, and structure-based design approach for this new class of compounds are discussed. [Copyright &y& Elsevier]

Abstract: A general procedure is described for the preparation of 6-substituted-5-hydroxy-3-oxo-2,3-dihydro-pyridazine-4-carboxylic acid ethyl esters (6-substituted-5-hydroxy-3(2H)-pyridazinone-4-carboxylic acid ethyl esters). These compounds are shown to undergo selective alkylation at the 2-position in moderate to good yields (19–77%) to afford 2,6-disubstituted-5-hydroxy-3-oxo-2,3-dihydro-pyridazine-4-carboxylic acid ethyl esters (2,6-disubstituted-5-hydroxy-3(2H)-pyridazinone-4-carboxylic acid ethyl esters). [Copyright &y& Elsevier]

Abstract: A general procedure is described for the regiospecific preparation of 1-substituted-5-hydroxy-1H-pyrazoles containing differentiated ester moieties at the 3- and 4-positions. This process involves the coupling of monosubstituted benzyl carbazates with various malonyl chlorides or acids, deprotection of the coupling products via catalytic hydrogenation, and subsequent derivatization of the resulting hydrazides with monoalkyl oxalyl chlorides. The 5-hydroxy-1H-pyrazoles are readily transformed to the corresponding trifluoromethane sulfonates, which undergo palladium-mediated Suzuki coupling with a variety of boronic acids (aryl, heteroaryl, and alkenyl) in moderate to excellent yields (24–92%). The ester groups present in one of the resulting 1,5-disubstituted-1H-pyrazoles are further modified by selective hydrolysis or conversion to the corresponding dicarboxylic acid derivative followed by selective mono-esterification. [Copyright &y& Elsevier]