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 identification of sulfonamido-aryl ethers as potent bradykinin B1 receptor antagonists from a approximately 60,000 member encoded combinatorial library are reported. Two distinct series of compounds exhibiting different structure-activity relationships were identified in a bradykinin B1 whole-cell receptor-binding assay. Specific examples exhibit K(i) values of approximately 10nM.
Asunto(s)
Antagonistas del Receptor de Bradiquinina B1 , Éteres/síntesis química , Sulfonamidas/síntesis química , Animales , Línea Celular , Técnicas Químicas Combinatorias , Humanos , Bibliotecas de Moléculas Pequeñas , Relación Estructura-Actividad , Sulfonamidas/farmacologíaRESUMEN
We describe in full the first synthesis of the potent insect antifeedant azadirachtin through a highly convergent approach. An O-alkylation reaction is used to unite decalin ketone and propargylic mesylate fragments, after which a Claisen rearrangement constructs the central C8-C14 bond in a stereoselective fashion. The allene which results from this sequence then enables a second critical carbon-carbon bond forming event whereby the [3.2.1] bicyclic system, present in the natural product, is generated via a 5-exo-radical cyclisation process. Finally, using knowledge gained through our early studies into the reactivity of the natural product, a series of carefully designed steps completes the synthesis of this challenging molecule.
