RESUMEN
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.
Asunto(s)
Adenosina/química , Antivirales/química , ADN Polimerasa Dirigida por ADN/química , Inhibidores de la Síntesis del Ácido Nucleico/química , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , ARN/química , Virus Sincitiales Respiratorios/enzimología , Virus Sincitiales Respiratorios/fisiología , Adenosina/síntesis química , Adenosina/farmacología , Antivirales/síntesis química , Antivirales/farmacología , Compuestos Aza/química , ADN Polimerasa Dirigida por ADN/metabolismo , Evaluación Preclínica de Medicamentos , Inhibidores de la Síntesis del Ácido Nucleico/síntesis química , Inhibidores de la Síntesis del Ácido Nucleico/farmacología , ARN/metabolismo , ARN Mitocondrial , ARN Polimerasa Dependiente del ARN/metabolismo , Virus Sincitiales Respiratorios/efectos de los fármacos , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
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.