RESUMO
Syntheses and nitric oxide synthase inhibitory activity of cyclic amidines containing 5,6- 6,6- and 7,6-fused systems are described. X-ray structure determination facilitated the assignment of the stereochemistry of the most active compounds perhydro-2-iminoisoquinoline (8a) and perhydro-2-iminopyrindine (10a). Both 8a and 10a are very potent inhibitors of iNOS, with excellent selectivity over eNOS and they are orally active in rats with long duration suitable for once or twice a day dosing.
Assuntos
Amidinas/química , Compostos Bicíclicos com Pontes/química , Inibidores Enzimáticos/administração & dosagem , Óxido Nítrico Sintase/antagonistas & inibidores , Piridinas/química , Quinolinas/química , Administração Oral , Amidinas/administração & dosagem , Animais , Compostos Bicíclicos com Pontes/administração & dosagem , Linhagem Celular , Inibidores Enzimáticos/farmacologia , Óxido Nítrico Sintase Tipo II , Piridinas/administração & dosagem , Quinolinas/administração & dosagem , RatosRESUMO
Synthesis of analogs containing more rigid bicyclic piperidine replacements for the 4-benzyloxycarbonyl-(ethyl)amino-piperidine moiety of the CCR5 antagonist structure, 1, is described. Although similar binding affinity to the lead was achieved with some analogs they were overall less potent anti-HIV agents suggesting that other features besides CCR5 binding are required for good anti-viral activity.
Assuntos
Fármacos Anti-HIV/síntese química , Antagonistas dos Receptores CCR5 , Sulfonas/síntese química , Fármacos Anti-HIV/farmacologia , Butanos/síntese química , Butanos/farmacologia , Relação Dose-Resposta a Droga , Concentração Inibidora 50 , Piperidinas/síntese química , Piperidinas/farmacologia , Relação Estrutura-Atividade , Sulfonas/farmacologia , Vírus/efeitos dos fármacosRESUMO
Syntheses and evaluation of pyrrolidin-2-imines and 1,3-thiazolidin-2-imines as inhibitors of nitric oxide synthase (NOS) are discussed. An extensive SAR was established for pyrrolidin-2-imines class of compounds. The amidines came out as the most potent inhibitors in addition to displaying selectivity.
Assuntos
Inibidores Enzimáticos/química , Iminas/química , Óxido Nítrico Sintase/antagonistas & inibidores , Pirrolidinas/química , Tiazóis/química , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/farmacologia , Iminas/farmacologia , Óxido Nítrico Sintase/metabolismo , Pirrolidinas/farmacologia , Tiazóis/farmacologiaRESUMO
Efforts toward the exploration of the title compounds as CCR5 antagonists are disclosed. The basis for such work stems from the fact that cellular proliferation of HIV-1 requires the cooperative assistance of both CCR5 and CD4 receptors. The synthesis and SAR of pyrrolidineacetic acid derivatives as CCR5 antagonists displaying potent binding and antiviral properties in a HeLa cell-based HIV-1 infectivity assay are discussed.