RESUMEN
An electrospinning process was optimized to produce fibers of micrometric size with different combinations of polymeric and surfactant materials to promote the dissolution rate of an insoluble drug: firocoxib. Scanning Electron Microscopy (SEM) showed that only some combinations of the proposed carrier systems allowed the production of suitable fibers and further fine optimization of the technique is also needed to load the drug. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) suggest that the drug is in an amorphous state in the final product. Drug amorphization, the fine dispersion of the active in the carriers, and the large surface area exposed to water interaction obtained through the electrospinning process can explain the remarkable improvement in the dissolution performance of firocoxib from the final product developed.
Asunto(s)
4-Butirolactona/análogos & derivados , Inhibidores de la Ciclooxigenasa 2/administración & dosificación , Inhibidores de la Ciclooxigenasa 2/química , Portadores de Fármacos , Nanofibras , Polímeros , Sulfonas/administración & dosificación , Sulfonas/química , Tensoactivos , 4-Butirolactona/administración & dosificación , 4-Butirolactona/química , Portadores de Fármacos/química , Nanofibras/química , Nanofibras/ultraestructura , Polímeros/química , Solubilidad , Espectroscopía Infrarroja por Transformada de Fourier , Tensoactivos/química , TermodinámicaRESUMEN
The synthesis and SAR of a new series of potent and selective dopamine D(3) receptor antagonists is reported. The introduction of a tricyclic [h]-fused benzazepine moiety on the recently disclosed scaffold of 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines is reported. A full rat pharmacokinetic characterization is also reported.
Asunto(s)
Benzazepinas/síntesis química , Benzazepinas/farmacología , Antagonistas de Dopamina/síntesis química , Antagonistas de Dopamina/farmacología , Receptores de Dopamina D3/antagonistas & inhibidores , Animales , Benzazepinas/química , Técnicas Químicas Combinatorias , Antagonistas de Dopamina/química , Diseño de Fármacos , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
High-throughput screening resulted in the identification of a series of novel motilin receptor agonists with relatively low molecular weights. The series originated from an array of biphenyl derivatives designed to target 7-transmembrane (7-TM) receptors. Further investigation of the structure-activity relationship within the series resulted in the identification of compound (22) as a potent and selective agonist at the motilin receptor.
Asunto(s)
Receptores de la Hormona Gastrointestinal/agonistas , Receptores de la Hormona Gastrointestinal/química , Receptores de Neuropéptido/agonistas , Receptores de Neuropéptido/química , Animales , Sitios de Unión , Membrana Celular/metabolismo , Química Farmacéutica/métodos , Técnicas Químicas Combinatorias , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Modelos Químicos , Estructura Molecular , Receptores Acoplados a Proteínas G/metabolismo , Proteínas Recombinantes/química , Relación Estructura-ActividadRESUMEN
Optimisation of urea (5), identified from high throughput screening and subsequent array chemistry, has resulted in the identification of pyridine carboxamide (33) which is a potent motilin receptor agonist possessing favourable physicochemical and ADME profiles. Compound (33) has demonstrated prokinetic-like activity both in vitro and in vivo in the rabbit and therefore represents a promising novel small molecule motilin receptor agonist for further evaluation as a gastroprokinetic agent.
Asunto(s)
Carbono/química , Piridinas/química , Receptores de la Hormona Gastrointestinal/agonistas , Receptores de Neuropéptido/agonistas , Animales , Química Farmacéutica/métodos , Diseño de Fármacos , Gastrinas/química , Humanos , Concentración 50 Inhibidora , Cinética , Modelos Químicos , Piridinas/síntesis química , Piridinas/farmacología , Conejos , Ratas , Receptores de la Hormona Gastrointestinal/química , Receptores de Neuropéptido/químicaRESUMEN
trans-6-Aminocyclohept-3-enols 18 and ent-18 are new designed polyfunctionalized chiral building blocks for piperidine alkaloids synthesis and are prepared in high yields from the enzymatically derived cyclohept-3-ene-1,6-diol monoacetate (-)-8. Efficient highly enantioselective syntheses of cis-4-hydroxypipecolic acid (1) and piperidines 3 and 4, in both enantiomeric forms, are described. [reaction: see text]