RESUMEN
Herein we describe the optimization of a series of PDE4 inhibitors, with special focus on solubility and pharamcokinetics, to clinical compound 2, 4-(8-(3-fluorophenyl)-1,7-naphthyridin-6-yl)transcyclohexanecarboxylic acid. Although compound 2 produces emesis in humans when given as a single dose, its exemplary pharmacokinetic properties enabled a novel dosing regime comprising multiple escalating doses and the resultant achievement of high plasma drug levels without associated nausea or emesis.
Asunto(s)
Ácidos Ciclohexanocarboxílicos/química , Naftiridinas/química , Inhibidores de Fosfodiesterasa 4/química , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Animales , Ácidos Ciclohexanocarboxílicos/farmacocinética , Ácidos Ciclohexanocarboxílicos/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Naftiridinas/farmacocinética , Naftiridinas/farmacología , Náusea/inducido químicamente , Inhibidores de Fosfodiesterasa 4/farmacocinética , Inhibidores de Fosfodiesterasa 4/farmacología , Ratas , Solubilidad , Relación Estructura-Actividad , Termodinámica , Vómitos/inducido químicamenteRESUMEN
The solubility-driven optimization of a series of 1,7-napthyridine phosphodiesterase-4 inhibitors is described. Directed structural changes resulted in increased aqueous solubility, enabling superior pharmacokinetic properties with retention of PDE4 inhibition. A range of potent and orally bioavailable compounds with good in vivo efficacy in animal models of inflammation and reduced emetic potential compared to previously described drugs were synthesized. Compound 2d was taken forward as a clinical candidate for the treatment of COPD.
Asunto(s)
Inhibidores de Fosfodiesterasa 4/química , Inhibidores de Fosfodiesterasa 4/farmacología , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Espectroscopía de Resonancia Magnética , Ratones , Modelos Moleculares , Inhibidores de Fosfodiesterasa 4/farmacocinética , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Ratas , Solubilidad , Vómitos/tratamiento farmacológicoRESUMEN
The synthesis and SAR of 5-heterocycle-substituted aminothiazole adenosine receptor antagonists is described. Several compounds show high affinity and selectivity for the A2B and A3 receptors. One compound (5f) shows good ADME properties in the rat and as such may be an important new compound in testing the current hypotheses proposing a therapeutic role for a dual A2B/A3 antagonist in allergic diseases.