RESUMO
A major resistance mechanism in Gram-negative bacteria is the production of ß-lactamase enzymes. Originally recognized for their ability to hydrolyze penicillins, emergent ß-lactamases can now confer resistance to other ß-lactam drugs, including both cephalosporins and carbapenems. The emergence and global spread of ß-lactamase-producing multi-drug-resistant "superbugs" has caused increased alarm within the medical community due to the high mortality rate associated with these difficult-to-treat bacterial infections. To address this unmet medical need, we initiated an iterative program combining medicinal chemistry, structural biology, biochemical testing, and microbiological profiling to identify broad-spectrum inhibitors of both serine- and metallo-ß-lactamase enzymes. Lead optimization, beginning with narrower-spectrum, weakly active compounds, provided 20 (VNRX-5133, taniborbactam), a boronic-acid-containing pan-spectrum ß-lactamase inhibitor. In vitro and in vivo studies demonstrated that 20 restored the activity of ß-lactam antibiotics against carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Enterobacteriaceae. Taniborbactam is the first pan-spectrum ß-lactamase inhibitor to enter clinical development.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Ácidos Borínicos/química , Ácidos Borínicos/farmacologia , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Inibidores de beta-Lactamases/química , Inibidores de beta-Lactamases/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/uso terapêutico , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Ácidos Borínicos/síntese química , Ácidos Borínicos/uso terapêutico , Carbapenêmicos/farmacologia , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/uso terapêutico , Humanos , Camundongos , Modelos Moleculares , Resistência beta-Lactâmica , Inibidores de beta-Lactamases/síntese química , Inibidores de beta-Lactamases/uso terapêuticoRESUMO
A series of 4,5-diarylimidazoline libraries were prepared using high-throughput solid-phase and microwave techniques. The compounds were evaluated as P2X(7) antagonists and their SAR is described.
