RESUMEN
An improved and efficient method for the preparation of torezolid based on Suzuki cross-coupling reaction as the key step was developed on a gram scale in five steps. The total yield was 44% and the optical purity of torezolid by the improved method was above 99%.
Asunto(s)
Antibacterianos/síntesis química , Oxazolidinonas/química , Tetrazoles/química , Antibacterianos/química , Catálisis , Complejos de Coordinación/química , Espectroscopía de Resonancia Magnética , Oxazolidinonas/síntesis química , Paladio/química , Tetrazoles/síntesis químicaRESUMEN
A series of xanthine compounds derived from the previous hit 20i with modification on the terminal side chain was discovered through ring formation strategy. Systematic optimization of the compounds with rigid heterocycles in the hydrophobic side chain led to the new lead compound HBK001 (21h) with the improved DPP-IV inhibition and moderate GPR119 agonism activity in vitro. As a continuing work to further study the PK and PD profiles, 21h and its hydrochloride (22) were synthesized on grams scale and evaluated on the ADME/T and oral glucose tolerance test (OGTT) in ICR mice. Compound 22 showed the improved bioavailability and blood glucose-lowering effect in vivo compared to its free base 21h probably attributed to its improved solubility and permeability. The preliminary toxicity studies on compound 22 exhibited that the result of mini-Ames was negative and the preliminary acute toxicity LD50 in mice was above 1.5 g/kg, while it showed moderate inhibition on hERG channel with IC50 4.9 µM maybe due to its high lipophilicity. These findings will be useful for the future drug design for more potent and safer dual ligand targeting DPP-IV and GPR119 for the treatment of diabetes.
Asunto(s)
Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Hipoglucemiantes/farmacología , Piperidinas/farmacología , Receptores Acoplados a Proteínas G/agonistas , Xantina/farmacología , Animales , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Inhibidores de la Dipeptidil-Peptidasa IV/química , Relación Dosis-Respuesta a Droga , Prueba de Tolerancia a la Glucosa , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Ratones , Ratones Endogámicos ICR , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Receptores Acoplados a Proteínas G/metabolismo , Relación Estructura-Actividad , Xantina/síntesis química , Xantina/químicaRESUMEN
A series of xanthine derivatives as potent dual ligands targeting DPP-IV and GPR119 was discovered through an approach of the merged pharmacophores of GPR119 agonists and DPP-IV inhibitor linagliptin. Systematic optimization of general structure 5 led to the identification of compound 20i with selective DPP-IV inhibition, good GPR119 agonism activity and favorable metabolic stability. Docking study was performed to elucidate the potent DPP-IV inhibition of 20i. Compound 20i may serve as a tool compound for further design of anti-diabetic drugs targeting both DPP-IV and GPR119.