RESUMO
ß-Lactamase inhibitors with a bicyclic urea core and a variety of heterocyclic side chains were prepared and evaluated as potential partners for combination with imipenem to overcome class A and C ß-lactamase mediated antibiotic resistance. The piperidine analog 3 (MK-7655) inhibited both class A and C ß-lactamases in vitro. It effectively restored imipenem's activity against imipenem-resistant Pseudomonas and Klebsiella strains at clinically achievable concentrations. A combination of MK-7655 and Primaxin® is currently in phase II clinical trials for the treatment of Gram-negative bacterial infections.
Assuntos
Compostos Azabicíclicos/química , Compostos Azabicíclicos/farmacologia , Cilastatina/química , Descoberta de Drogas , Inibidores Enzimáticos/química , Imipenem/química , Inibidores de beta-Lactamases , Cilastatina/farmacologia , Combinação Imipenem e Cilastatina , Cristalografia por Raios X , Combinação de Medicamentos , Farmacorresistência Bacteriana/efeitos dos fármacos , Imipenem/farmacologia , Concentração Inibidora 50 , Klebsiella/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Modelos Biológicos , Pseudomonas/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Amino-anthranilic acid derivatives have been identified as a new class of low serum shifted, high affinity full agonists of the human orphan G-protein-coupled receptor GPR109a with improved ADME properties.
Assuntos
Descoberta de Drogas , Receptores Acoplados a Proteínas G/agonistas , Animais , Flúor/química , Humanos , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Niacina/síntese química , Niacina/química , Niacina/farmacologia , Piridinas/síntese química , Piridinas/química , Ratos , Ratos Sprague-Dawley , Receptores NicotínicosRESUMO
[reaction: see text] Glucal 3-carbamates 1 and 7 underwent oxidative cyclization with iodobenzene diacetate or iodosobenzene in the presence of Rh2(OAc)4, providing mannosamine 2-N,3-O-oxazolidinones. With iodosobenzene, incorporation of 4-penten-1-ol provided a readily separable anomeric mixture of n-pentenyl glycosides, with the anomers exhibiting pronounced differences in reactivity as glycosyl donors. N-acylation of the sugar oxazolidinones led to alpha-selective glycosyl donors for the elaboration of various 2-mannosamine frameworks. Alternatively, the anomeric n-pentenyl glycosides of N-Cbz 2-mannosamine oxazolidinones were converted separately to oxazolidinone-opened derivatives 28alpha and 28beta. These served as stereoconvergent glycosyl donors, and the alpha-linked products were readily advanced to a variety of N-acetylmannosamine (ManNAc) frameworks, using an intramolecular O-->N acetyl transfer as the final step.