title: 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.
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.
authors: Alios BioPharma, Inc. , 260 East Grand Avenue, South San Francisco, California 94080, United States.
authors: Guangyi
authors: G
authors: Wang
authors: Jerome
authors: J
authors: Deval
authors: Jin
authors: J
authors: Hong
authors: Natalia
authors: N
authors: Dyatkina
authors: Marija
authors: M
authors: Prhavc
authors: Joshua
authors: J
authors: Taylor
authors: Amy
authors: A
authors: Fung
authors: Zhinan
authors: Z
authors: Jin
authors: Sarah K
authors: SK
authors: Stevens
authors: Vladimir
authors: V
authors: Serebryany
authors: Jyanwei
authors: J
authors: Liu
authors: Qingling
authors: Q
authors: Zhang
authors: Yuen
authors: Y
authors: Tam
authors: Sushmita M
authors: SM
authors: Chanda
authors: David B
authors: DB
authors: Smith
authors: Julian A
authors: JA
authors: Symons
authors: Lawrence M
authors: LM
authors: Blatt
authors: Leo
authors: L
authors: Beigelman
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006224:Cricetinae; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000882:Haplorhini; D006801:Humans; D008297:Male; D008968:Molecular Conformation; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy* / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000187:drug effects* / Q000201:enzymology*; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011355:Prodrugs; D003841:Deoxycytidine; C000597470:4'-chloromethyl-2'-deoxy-3',5'-di-O-isobutyryl-2'-fluorocytidine; D011065:Poly(ADP-ribose) Polymerases; D012321:DNA-Directed RNA Polymerases; D004259:DNA-Directed DNA Polymerase