RESUMEN
Conformationally constrained tetracyclic fluoroquinolones (FQs) were synthesized and profiled for their microbiological spectrum. The installation of a seven-membered ring between the pyrrolidine substituents and the C8 position on the FQ core scaffold resulted in a remarkable enhancement of microbiological potency toward both Gram-positive and Gram-negative bacteria. Focused optimization of seven-membered ring composition, stereochemistry, and amine placement led to the discovery of the two lead compounds that were selected for further progression.
Asunto(s)
Fluoroquinolonas/síntesis química , Fluoroquinolonas/farmacología , Tetraciclinas/síntesis química , Tetraciclinas/farmacología , Acinetobacter baumannii/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Pseudomonas aeruginosa/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
A series of oxadiazolone bioisosteres of pregabalin 1 and gabapentin 2 were prepared, and several were found to exhibit similar potency for the alpha(2)-delta subunit of voltage-gated calcium channels. Oxadiazolone 9 derived from 2 achieved low brain uptake but was nevertheless active in models of osteoarthritis. The high clearance associated with compound 9 was postulated to be a consequence of efflux by OAT and/or OCT, and was attenuated on co-administration with cimetidine or probenecid.
Asunto(s)
Aminas , Ácidos Ciclohexanocarboxílicos , Osteoartritis/tratamiento farmacológico , Oxadiazoles/química , Oxadiazoles/uso terapéutico , Ácido gamma-Aminobutírico/análogos & derivados , Animales , Encéfalo/metabolismo , Interacciones Farmacológicas , Quimioterapia Combinada , Gabapentina , Factores de Transcripción de Octámeros , Transportadores de Anión Orgánico , Oxadiazoles/farmacología , Pregabalina , RatasRESUMEN
Pregabalin exhibits robust activity in preclinical assays indicative of potential antiepileptic, anxiolytic, and antihyperalgesic clinical efficacy. It binds with high affinity to the alpha(2)-delta subunit of voltage-gated calcium channels and is a substrate of the system L neutral amino acid transporter. A series of pregabalin analogues were prepared and evaluated for their alpha(2)-delta binding affinity as demonstrated by their ability to inhibit binding of [(3)H]gabapentin to pig brain membranes and for their potency to inhibit the uptake of [(3)H]leucine into CHO cells, a measure of their ability to compete with the endogenous substrate at the system L transporter. Compounds were also assessed in vivo for their ability to promote anxiolytic, analgesic, and anticonvulsant actions. These studies suggest that distinct structure activity relationships exist for alpha(2)-delta binding and system L transport inhibition. However, both interactions appear to play an important role in the in vivo profile of these compounds.