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

作者：Wang Guangyi^*; Deval Jerome; Hong Jin; Dyatkina Natalia; Prhavc Marija; Taylor Joshua; Fung Amy; Jin Zhinan; Stevens Sarah K; Serebryany Vladimir; Liu Jyanwei; Zhang Qingling; Tam Yuen; Chanda Sushmita M; Smith David B; Symons Julian A; Blatt Lawrence M; Beigelman Leo

来源：Journal of Medicinal Chemistry, 2015, 58(4): 1862-1878.

DOI：10.1021/jm5017279

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 mu M. The 5'-triphosphate of 2c (2c-TP) inhibited RSV polymerase with an IC50 of 0.02 mu M without appreciable inhibition of human DNA and RNA polymerases at 100 mu M. 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.

• 出版日期2015-2-26