RESUMEN
The optimization of the pharmacokinetic performance of various 2-pyridone-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors following oral administration to either beagle dogs or CM-monkeys is described. The molecules described in this work are composed of a 2-pyridone-containing peptidomimetic binding determinant and an alpha,beta-unsaturated ester Michael acceptor moiety which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. Modification of the ester contained within these compounds is detailed along with alteration of the P(2) substituent present in the peptidomimetic portion of the inhibitors. The pharmacokinetics of several inhibitors in both dogs and monkeys are described (7 h plasma concentrations after oral administration) along with their human plasma stabilities, stabilities in incubations with human, dog, and monkey microsomes and hepatocytes, Caco-2 permeabilities, and aqueous solubilities. Compounds containing an alpha,beta-unsaturated ethyl ester fragment and either an ethyl or propargyl P(2) moiety displayed the most promising combination of 3C enzyme inhibition (k(obs)/[I] 170 000-223 000 M(-1) s(-1)), antiviral activity (EC(50) = 0.047-0.058 microM, mean vs seven HRV serotypes), and pharmacokinetics following oral administration (7 h dog plasma levels = 0.248-0.682 microM; 7 h CM-monkey plasma levels = 0.057-0.896 microM).
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Cisteína Endopeptidasas/metabolismo , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Piridonas/síntesis química , Piridonas/farmacología , Rhinovirus/enzimología , Proteínas Virales/metabolismo , Proteasas Virales 3C , Animales , Antivirales/farmacocinética , Disponibilidad Biológica , Proteínas Sanguíneas/metabolismo , Células CACO-2 , Perros , Diseño de Fármacos , Semivida , Hepatocitos/metabolismo , Humanos , Técnicas In Vitro , Indicadores y Reactivos , Macaca fascicularis , Espectroscopía de Resonancia Magnética , Masculino , Microsomas Hepáticos/metabolismo , Inhibidores de Proteasas/farmacocinética , Unión Proteica , Rhinovirus/efectos de los fármacos , Solubilidad , Relación Estructura-ActividadRESUMEN
This paper describes a convenient protocol for the regioselective sulfonylation of alpha-chelatable alcohols. Typically, the reaction of alpha-heterosubstituted alcohols with 1 equiv of p-TsCl and 1 equiv of Et(3)N in the presence of 2 mol % of Bu(2)SnO leads to rapid, regioselective, and exclusive monotosylation. The pK(a) of the amine was correlated to the reaction rate. A plausible mechanism for this reaction has been proposed on the basis of (119)Sn NMR studies.
