RESUMEN
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.
Asunto(s)
Amidinas/química , Compuestos Bicíclicos con Puentes/química , Inhibidores Enzimáticos/administración & dosificación , Óxido Nítrico Sintasa/antagonistas & inhibidores , Piridinas/química , Quinolinas/química , Administración Oral , Amidinas/administración & dosificación , Animales , Compuestos Bicíclicos con Puentes/administración & dosificación , Línea Celular , Inhibidores Enzimáticos/farmacología , Óxido Nítrico Sintasa de Tipo II , Piridinas/administración & dosificación , Quinolinas/administración & dosificación , RatasRESUMEN
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).
Asunto(s)
Óxido Nítrico Sintasa/antagonistas & inhibidores , Oxazepinas/síntesis química , Tiazepinas/síntesis química , Azirinas/síntesis química , Azirinas/farmacología , Dihidropiridinas/síntesis química , Dihidropiridinas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Óxido Nítrico Sintasa/metabolismo , Oxazepinas/farmacología , Tiazepinas/farmacologíaRESUMEN
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.
Asunto(s)
Inhibidores Enzimáticos/química , Iminas/química , Óxido Nítrico Sintasa/antagonistas & inhibidores , Pirrolidinas/química , Tiazoles/química , Evaluación Preclínica de Medicamentos/métodos , Inhibidores Enzimáticos/farmacología , Iminas/farmacología , Óxido Nítrico Sintasa/metabolismo , Pirrolidinas/farmacología , Tiazoles/farmacologíaRESUMEN
A series of isonicotinoyl-(L)-aminophenylalanine derivatives was prepared and evaluated as VLA-4 antagonists. These compounds exhibit subnanomolar binding affinity to VLA-4 and significant off-rates. The interplay between off-rate, protein binding and pharmacokinetics is discussed.
Asunto(s)
Integrina alfa4beta1/antagonistas & inhibidores , Fenilalanina/análogos & derivados , Fenilalanina/farmacología , Animales , Calcio/química , Calcio/farmacología , Quimiotaxis de Leucocito/efectos de los fármacos , Perros , Eosinófilos/efectos de los fármacos , Semivida , Humanos , Concentración 50 Inhibidora , Ácidos Isonicotínicos/sangre , Ácidos Isonicotínicos/síntesis química , Ácidos Isonicotínicos/farmacocinética , Ácidos Isonicotínicos/farmacología , Células Jurkat , Macaca mulatta , Manganeso/química , Manganeso/farmacología , Fenilalanina/sangre , Fenilalanina/farmacocinética , Unión Proteica , Ratas , Ratas Sprague-Dawley , Molécula 1 de Adhesión Celular Vascular/metabolismoRESUMEN
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.