A series of next in class small-molecule hepatitis C virus (HCV) NS5A inhibitors with picomolar potency containing 2-pyrrolidin-2-yl-5-{4-[4-(2-pyrrolidin-2-yl-1H-imidazol-5-yl)buta-1,3-diynyl]phenyl}-1H-imidazole cores was designed based on the SAR studies available for the reported NS5A inhibitors. Compound 13a (AV4025), with (S,S,S,S)-stereochemistry (EC50 = 3.4 ± 0.2 pM, HCV replicon genotype 1b), was dramatically more active than were the compounds with two (S)- and two (R)-chiral centers. Human serum did not significantly reduce the antiviral activity (<4-fold). Relatively favorable pharmacokinetic features and good oral bioavailability were observed during animal studies. Compound 13a was well tolerated in rodents (in mice, LD50 = 2326 mg/kg or higher), providing a relatively high therapeutic index. During safety, pharmacology and subchronic toxicity studies in rats and dogs, it was not associated with any significant pathological or clinical findings. This compound is currently being evaluated in phase I/II clinical trials for the treatment of HCV infection.
Based on the results presented in this study, AV5080 is a promising novel oral drug candidate for the treatment of influenza, including oseltamivir-resistant types. Further pre-clinical development of AV5080 is warranted.
“Click”
reactions have transformed the molecular
sciences. Augmenting cycloaddition reactions, sulfur(VI) fluoride
exchange (SuFEx) chemistry has diversified the landscape of molecular
assembly. Herein, we report a facile strategy to access SuFExable NH-pyrazoles via strain and catalyst-free 1,3-dipolar cycloadditions
of stabilized diazo compounds under mild conditions. Subsequent SuFEx
proceeds efficiently with various N- and O-nucleophiles. Access to SuFExable NH-pyrazolesa
class of compounds containing two common pharmacophoresenables
future opportunities within drug discovery, chemical biology, materials
chemistry, and related fields.
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