ABSTRACT
Novel 4'-substituted ß-d-2'-deoxy-2'-α-fluoro (2'd2'F) nucleoside inhibitors of respiratory syncytial virus (RSV) are reported. The introduction of 4'-substitution onto 2'd2'F nucleoside analogs resulted in compounds demonstrating potent cell based RSV inhibition, improved inhibition of the RSV polymerase by the nucleoside triphosphate metabolites, and enhanced selectivity over incorporation by mitochondrial RNA and DNA polymerases. Selectivity over the mitochondrial polymerases was found to be extremely sensitive to the specific 4'-substitution and not readily predictable. Combining the most potent and selective 4'-groups from N-nucleoside analogs onto a 2'd2'F C-nucleoside analog resulted in the identification of ß-D-2'-deoxy-2'-α-fluoro-4'-α-cyano-5-aza-7,9-dideaza adenosine as a promising nucleoside lead for RSV.
Subject(s)
Adenosine/chemistry , Antiviral Agents/chemistry , DNA-Directed DNA Polymerase/chemistry , Nucleic Acid Synthesis Inhibitors/chemistry , RNA-Dependent RNA Polymerase/antagonists & inhibitors , RNA/chemistry , Respiratory Syncytial Viruses/enzymology , Respiratory Syncytial Viruses/physiology , Adenosine/chemical synthesis , Adenosine/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Aza Compounds/chemistry , DNA-Directed DNA Polymerase/metabolism , Drug Evaluation, Preclinical , Nucleic Acid Synthesis Inhibitors/chemical synthesis , Nucleic Acid Synthesis Inhibitors/pharmacology , RNA/metabolism , RNA, Mitochondrial , RNA-Dependent RNA Polymerase/metabolism , Respiratory Syncytial Viruses/drug effects , Structure-Activity Relationship , Virus Replication/drug effectsABSTRACT
A unique tetrahydrofuran ether class of highly potent α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiators has been identified using rational and structure-based drug design. An acyclic lead compound, containing an ether-linked isopropylsulfonamide and biphenyl group, was pharmacologically augmented by converting it to a conformationally constrained tetrahydrofuran to improve key interactions with the human GluA2 ligand-binding domain. Subsequent replacement of the distal phenyl motif with 2-cyanothiophene to enhance its potency, selectivity, and metabolic stability afforded N-{(3S,4S)-4-[4-(5-cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide (PF-04958242, 3), whose preclinical characterization suggests an adequate therapeutic index, aided by low projected human oral pharmacokinetic variability, for clinical studies exploring its ability to attenuate cognitive deficits in patients with schizophrenia.