2. Academic Validation
  3. Discovery of 4'-chloromethyl-2'-deoxy-3',5'-di-O-isobutyryl-2'-fluorocytidine (ALS-8176), a first-in-class RSV polymerase inhibitor for treatment of human respiratory syncytial virus infection

Discovery of 4'-chloromethyl-2'-deoxy-3',5'-di-O-isobutyryl-2'-fluorocytidine (ALS-8176), a first-in-class RSV polymerase inhibitor for treatment of human respiratory syncytial virus infection

  • J Med Chem. 2015 Feb 26;58(4):1862-78. doi: 10.1021/jm5017279.
Guangyi Wang 1,  Jerome Deval,  Jin Hong,  Natalia Dyatkina,  Marija Prhavc,  Joshua Taylor,  Amy Fung,  Zhinan Jin,  Sarah K Stevens,  Vladimir Serebryany,  Jyanwei Liu,  Qingling Zhang,  Yuen Tam,  Sushmita M Chanda,  David B Smith,  Julian A Symons,  Lawrence M Blatt,  Leo Beigelman
Affiliations

Affiliation

  • 1 Alios BioPharma, Inc. , 260 East Grand Avenue, South San Francisco, California 94080, United States.
PMID: 25667954 DOI: 10.1021/jm5017279
Abstract

Respiratory syncytial virus (RSV) is a leading pathogen of childhood and is associated with significant morbidity and mortality. To date, ribavirin is the only approved small molecule drug, which has limited use. The only other RSV drug is palivizumab, a monoclonal antibody, which is used for RSV prophylaxis. Clearly, there is an urgent need for small molecule RSV drugs. This article reports the design, synthesis, anti-RSV activity, metabolism, and pharmacokinetics of a series of 4'-substituted cytidine nucleosides. Among tested compounds 4'-chloromethyl-2'-deoxy-2'-fluorocytidine (2c) exhibited the most promising activity in the RSV replicon assay with an EC50 of 0.15 μM. The 5'-triphosphate of 2c (2c-TP) inhibited RSV polymerase with an IC50 of 0.02 μM without appreciable inhibition of human DNA and RNA polymerases at 100 μM. ALS-8176 (71), the 3',5'-di-O-isobutyryl prodrug of 2c, demonstrated good oral bioavailability and a high level of 2c-TP in vivo. Compound 71 is a first-in-class nucleoside RSV polymerase inhibitor that demonstrated excellent anti-RSV efficacy and safety in a phase 2 clinical RSV challenge study.

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