RESUMO
Activation of the G-protein coupled receptor (GPCR) Takeda G-protein receptor 5 (TGR5), also known as G-protein bile acid receptor 1 (GPBAR1), has been shown to play a key role in pathways associated with diabetes, metabolic syndrome, and autoimmune disease. Nipecotamide 5 was identified as an attractive starting point after a high-throughput screen (HTS) for receptor agonists. A comprehensive hit-to-lead effort culminated in the discovery of 45h as a potent, selective, and bioavailable TGR5 agonist to test in preclinical metabolic disease models. In genetically obese mice (ob/ob), 45h was as effective as a dipeptidyl peptidase-4 (DPP-4) inhibitor at reducing peak glucose levels in an acute oral glucose tolerance test (OGTT), but this effect was lost upon chronic dosing.
Assuntos
Hipoglicemiantes/síntese química , Piperazinas/síntese química , Receptores Acoplados a Proteínas G/agonistas , Administração Oral , Animais , Disponibilidade Biológica , Descoberta de Drogas , Peptídeo 1 Semelhante ao Glucagon/análise , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Piperazinas/farmacologia , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Exenatide is a peptide incretin mimetic that has glucoregulatory actions associated with weight reduction. Previous reports demonstrated acute increases in blood pressure after systemic or intracerebroventricular administration of exenatide or glucagon like peptide 1 (GLP 1) in rats. However, there are limited studies testing the chronic effects of these peptides on arterial pressure and no reports showing the effects of these peptides to reverse hypertension in the context of the metabolic syndrome. METHODS: Thus, we examined the response to peripheral exenatide using telemetry in conscious, unrestrained rats under normotensive conditions and in a model of hypertension/metabolic syndrome induced by corticosterone. Rats were implanted with either corticosterone or wax (control) pellets, followed 14 days later by the additional implantation of pumps to deliver exenatide (1 microg/kg per day) or vehicle for 7 days. RESULTS: The 21-day corticosterone treatment produced hypertriglyceridemia, visceral fat deposition, hyperglycemia, insulin resistance, and an elevation of mean arterial blood pressure (MAP) by 14 +/- 1 mmHg. Exenatide significantly reversed corticosterone-induced increases in blood pressure and this normalization occurred independently from change in body weight. Additionally, exenatide reduced MAP by 5 +/- 3 mmHg in normotensive control rats. CONCLUSIONS: These results are the first demonstration of a durable antihypertensive effect of exenatide in a glucocorticoid-induced model of the metabolic syndrome.