RESUMO
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.
Assuntos
Fluoroquinolonas/síntese química , Fluoroquinolonas/farmacologia , Tetraciclinas/síntese química , Tetraciclinas/farmacologia , Acinetobacter baumannii/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pseudomonas aeruginosa/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Aminas , Ácidos Cicloexanocarboxílicos , Osteoartrite/tratamento farmacológico , Oxidiazóis/química , Oxidiazóis/uso terapêutico , Ácido gama-Aminobutírico/análogos & derivados , Animais , Encéfalo/metabolismo , Interações Medicamentosas , Quimioterapia Combinada , Gabapentina , Fatores de Transcrição de Octâmero , Transportadores de Ânions Orgânicos , Oxidiazóis/farmacologia , Pregabalina , RatosRESUMO
Novel 2,4-diaminopyrimidine-based small molecule renin inhibitors are disclosed. Through high throughput screening, parallel synthesis, X-ray crystallography, and structure based drug design, we have developed the first non-chiral, non-peptidic, small molecular template to possess moderate potency against renin. The designed compounds consist of a novel 6-ethyl-5-(1,2,3,4-tetrahydroquinolin-7-yl)pyrimidine-2,4-diamine ring system that exhibit moderate potency (IC(50): 91-650 nM) against renin while remaining 'Rule-of-five' compliant.
Assuntos
Química Farmacêutica/métodos , Pirimidinas/química , Renina/antagonistas & inibidores , Animais , Cristalografia por Raios X , Desenho de Fármacos , Concentração Inibidora 50 , Modelos Químicos , Modelos Moleculares , Conformação Molecular , Pirimidinas/síntese química , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
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.