RESUMO
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.
Assuntos
4-Butirolactona/análogos & derivados , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/química , Portadores de Fármacos , Nanofibras , Polímeros , Sulfonas/administração & dosagem , Sulfonas/química , Tensoativos , 4-Butirolactona/administração & dosagem , 4-Butirolactona/química , Portadores de Fármacos/química , Nanofibras/química , Nanofibras/ultraestrutura , Polímeros/química , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Tensoativos/química , TermodinâmicaRESUMO
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.
Assuntos
Benzazepinas/síntese química , Benzazepinas/farmacologia , Antagonistas de Dopamina/síntese química , Antagonistas de Dopamina/farmacologia , Receptores de Dopamina D3/antagonistas & inibidores , Animais , Benzazepinas/química , Técnicas de Química Combinatória , Antagonistas de Dopamina/química , Desenho de Fármacos , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Receptores dos Hormônios Gastrointestinais/agonistas , Receptores dos Hormônios Gastrointestinais/química , Receptores de Neuropeptídeos/agonistas , Receptores de Neuropeptídeos/química , Animais , Sítios de Ligação , Membrana Celular/metabolismo , Química Farmacêutica/métodos , Técnicas de Química Combinatória , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Modelos Químicos , Estrutura Molecular , Receptores Acoplados a Proteínas G/metabolismo , Proteínas Recombinantes/química , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Carbono/química , Piridinas/química , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores de Neuropeptídeos/agonistas , Animais , Química Farmacêutica/métodos , Desenho de Fármacos , Gastrinas/química , Humanos , Concentração Inibidora 50 , Cinética , Modelos Químicos , Piridinas/síntese química , Piridinas/farmacologia , Coelhos , Ratos , Receptores dos Hormônios Gastrointestinais/química , Receptores de Neuropeptídeos/químicaRESUMO
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]