491585-44-5

Upstream product

• 22264-50-2 1-aminocyclobutane-1-carboxylic acid 
• 735287-43-1 1-amino-cyclobutanecarbonyl chloride hydrochloride 
• 5048-82-8 ethyl 4-aminocinnamate 
• 491585-38-7 C₁₁H₂₁NO₄Si 
• 5048-82-8 (E)-ethyl 3-(4-aminophenyl)acrylate 

Downstream Products

• 1427549-59-4 ethyl (2E)-3-[4-[[1-[[3-cyclohexyl-2-(4-fluorophenyl)-1-methyl-imidazo[1,2-b]pyrazole-7-carbonyl]amino]cyclobutanecarbonyl]amino]phenyl]prop-2-enoate 
• 494856-80-3 C₃₂H₃₂N₄O₅ 
• 1393929-35-5 C₃₈H₃₆N₄O₄ 
• 1393929-34-4 C₃₈H₃₆N₄O₄ 
• 494857-05-5 C₃₃H₃₃N₅O₄ 
• 494856-35-8 C₃₃H₃₃N₅O₄ 
• 494856-36-9 C₃₄H₃₄N₄O₄ 
• 1393929-33-3 C₃₅H₃₆N₄O₅ 
• 1393929-32-2 C₃₅H₃₆N₄O₄ 
• 494856-40-5 C₃₅H₃₆N₄O₅ 
• 1393929-30-0 C₃₄H₃₅N₅O₄ 
• 494857-17-9 C₃₅H₃₆N₄O₅ 
• 494856-38-1 C₃₅H₃₃F₃N₄O₄ 

Relevant academic research and scientific papers

Discovery of the first thumb pocket 1 NS5B polymerase inhibitor (BILB 1941) with demonstrated antiviral activity in patients chronically infected with genotype 1 hepatitis C virus (HCV)

Combinations of direct acting antivirals (DAAs) that have the potential to suppress emergence of resistant virus and that can be used in interferon-sparing regimens represent a preferred option for the treatment of chronic HCV infection. We have discovered allosteric (thumb pocket 1) non-nucleoside inhibitors of HCV NS5B polymerase that inhibit replication in replicon systems. Herein, we report the late-stage optimization of indole-based inhibitors, which began with the identification of a metabolic liability common to many previously reported inhibitors in this series. By use of parallel synthesis techniques, a sparse matrix of inhibitors was generated that provided a collection of inhibitors satisfying potency criteria and displaying improved in vitro ADME profiles. "Cassette" screening for oral absorption in rat provided a short list of potential development candidates. Further evaluation led to the discovery of the first thumb pocket 1 NS5B inhibitor (BILB 1941) that demonstrated antiviral activity in patients chronically infected with genotype 1 HCV.

Importance of ligand bioactive conformation in the discovery of potent indole-diamide inhibitors of the hepatitis C virus NS5B

Significant advances have led to receptor induced-fit and conformational selection models for describing bimolecular recognition, but a more comprehensive view must evolve to also include ligand shape and conformational changes. Here, we describe an example where a ligand's "structural hinge" influences potency by inducing an "L-shape" bioactive conformation, and due to its solvent exposure in the complex, reasonable conformation-activity-relationships can be qualitatively attributed. From a ligand design perspective, this feature was exploited by successful linker hopping to an alternate "structural hinge" that led to a new and promising chemical series which matched the ligand bioactive conformation and the pocket bioactive space. Using a combination of X-ray crystallography, NMR and modeling with support from binding-site resistance mutant studies and photoaffinity labeling experiments, we were able to derive inhibitor-polymerase complexes for various chemical series.

VIRAL POLYMERASE INHIBITORS

An isomer, enantiomer, diastereoisomer or tautomer of a compound, represented by formula (I): wherein wherein A, B, R2, R3, L, M1, M2, M3, M4, Y1, Y0, Z and Sp are as defined in claim 1, or a salt thereof, as an inhibitor of HCV NS5B polymerase.