RESUMEN
A series of quinoline/naphthalene-difluoromethylphosphonates were prepared and were found to be potent PTP1B inhibitors. Most of these compounds bearing polar functionalities or large lipophilic residues did not show appreciable oral bioavailability in rodents while small and less polar analogs displayed moderate to good oral bioavailability. The title compound was found to have the best overall potency and pharmacokinetic profile and was found to be efficacious in animal models of diabetes and cancer.
Asunto(s)
Hidrocarburos Halogenados/síntesis química , Hidrocarburos Halogenados/farmacología , Naftalenos/síntesis química , Naftalenos/farmacología , Organofosfonatos/síntesis química , Organofosfonatos/farmacología , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Animales , Técnicas Químicas Combinatorias , Diabetes Mellitus/inducido químicamente , Modelos Animales de Enfermedad , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Haplorrinos , Hidrocarburos Halogenados/química , Ratones , Estructura Molecular , Naftalenos/química , Neoplasias/inducido químicamente , Organofosfonatos/química , RatasRESUMEN
A series of benzotriazole phenyldifluoromethylphosphonic acids were found to be potent PTP-1B inhibitors. Molecular modeling on the X-ray crystal structure of the lead structure led to the design of potent PTP-1B inhibitors that show moderate selectivity against TC-PTP, a very closely related protein tyrosine phosphatase.