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
A series of 3- and 5-imino analogs from oxazepane, thiazepane, and diazepane was prepared and evaluated as inhibitors of human nitric oxide synthesis (NOS). The most potent iNOS inhibitor was the thiazepane analog 25 (IC(50) = 0.19 microM).
Assuntos
Óxido Nítrico Sintase/antagonistas & inibidores , Oxazepinas/síntese química , Tiazepinas/síntese química , Azirinas/síntese química , Azirinas/farmacologia , Di-Hidropiridinas/síntese química , Di-Hidropiridinas/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Óxido Nítrico Sintase/metabolismo , Oxazepinas/farmacologia , Tiazepinas/farmacologiaRESUMO
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
Preparation and screening of mixture libraries based on a 2-arylindole scaffold resulted in the discovery of potent ligands for a variety of G-protein coupled receptors.