RESUMO
Following the identification of a potent IRAK inhibitor through routine project cross screening, a novel class of IRAK-4 inhibitor was established. The SAR of imidazo[1,2-a]pyridino-pyridines and benzimidazolo-pyridines was explored.
Assuntos
Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Avaliação Pré-Clínica de Medicamentos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridinas/síntese química , Piridinas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Previous studies have shown that in male rats, exposure to maternal protein restriction either in utero or whilst suckling can have profound effects on both longevity and kidney telomere lengths. This study monitored albuminuria longitudinally in male rats whose mothers had been protein restricted either during pregnancy or lactation. METHODS: Pregnant Wistar rats were fed either a 20% ('control') or an 8% protein ('low protein') diet. At two days of age some of the pups were cross-fostered to dams fed the diet that was not given to their biological mothers. At weaning all pups were fed standard chow. Urine samples were collected for the measurement of albumin and creatinine at monthly intervals from two months-of-age. Longitudinal analysis was then performed using repeated measures analysis of variance. RESULTS: Overall estimated marginal geometric mean (95 % confidence interval) urine albumin to creatinine ratios were: control animals 79.5 (57.2 to approximately 110.6) g/mol (n = 6 litters, 24 animals in total), those exposed in utero to maternal protein restriction 71.0 (47.4 to approximately 106.5) (n = 4 litters, 16 animals in total), those exposed to maternal protein restriction whilst suckling 21.2 (14.7 to approximately 30.4) (n = 5 litters, 20 animals in total) (p < 0.001). These latter animals had lower albumin to creatinine ratios than either of the two other groups (both p < 0.001), which had ratios that were indistinguishable from each other (p = 1.0). Similar results were gained using 24 h. urine albumin excretion rates. These differences became evident from three months-of-age and were long-lasting. CONCLUSION: Animals exposed to maternal protein restriction whilst suckling exhibited lower urine albumin excretions during much of adult life. As urine albumin can be nephrotoxic, these rats therefore appeared to be relatively protected against future nephron damage like that previously observed in animals exposed to maternal protein restriction in utero.
Assuntos
Envelhecimento/metabolismo , Albuminúria/metabolismo , Proteínas Alimentares/administração & dosagem , Proteínas Alimentares/metabolismo , Efeitos Tardios da Exposição Pré-Natal/urina , Envelhecimento/efeitos dos fármacos , Albuminúria/diagnóstico , Albuminúria/prevenção & controle , Animais , Animais Lactentes/metabolismo , Feminino , Estudos Longitudinais , Masculino , Gravidez , Ratos , Ratos WistarRESUMO
The development of a series of novel aminopyrimidines as inhibitors of c-Jun N-terminal kinases is described. The synthesis, in vitro inhibitory values for JNK1, JNK2 and CDK2, and the in vitro inhibitory value for a c-Jun cellular assay are discussed.