Division of Endocrinology & Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
55pharma Drug Discovery & Development AG, Vienna, Austria.
Diabetes Obes Metab. 2017 Aug;19(8):1088-1096. doi: 10.1111/dom.12914. Epub 2017 Apr 3.
55P0251 is a novel compound with blood glucose lowering activity in mice, which has been developed from a molecular backbone structure found in herbal remedies. We here report its basic pharmacological attributes and initial progress in unmasking the mode of action.
Pharmacokinetic properties of 55P0251 were portrayed in several species. First efforts to elucidate the glucose lowering mechanism in rodents included numerous experimental protocols dealing with glucose tolerance, insulin secretion from isolated pancreatic islets and comparison to established drugs.
A single oral dose of 55P0251 improved glucose tolerance in mice with an ED between 1.5 and 2 mg/kg (reductions in areas under the curve, 1 mg/kg, -18%; 5 mg/kg, -30%; 27 mg/kg, -47%). Pharmacokinetic studies revealed attractive attributes, including a plasma half-life of approximately 3 hours and a bioavailability of approximately 58% in rats. 55P0251 amplified glucose stimulated insulin release from isolated mouse islets and improved glucose tolerance via increased insulin secretion in rats (increase in area under the insulin curve, +184%). Unlike sulfonylureas and glinides, 55P0251 hardly stimulated insulin release under basal conditions and did not induce hypoglycaemia in vivo, but it amplified the secretory response to glucose and other insulinotropic stimuli (KCl, glucagon-like peptide-1). Comparison to established anti-diabetic agents and examination of interaction with molecular targets (K channel, dipeptidyl peptidase-4, glucagon-like peptide-1 receptor) excluded molecular mechanisms addressed by presently marketed drugs.
55P0251 is a novel compound that potently counteracts hyperglycaemia in rodents via amplification of glucose-stimulated insulin release.
55P0251 是一种在小鼠中具有降血糖活性的新型化合物，它是从草药治疗中发现的分子骨架结构开发而来的。我们在此报告其基本的药理学特性，并初步揭示其作用机制。
在几种物种中描述了 55P0251 的药代动力学特性。阐明啮齿动物中降血糖机制的最初努力包括许多实验方案，涉及葡萄糖耐量、分离胰岛的胰岛素分泌以及与已建立的药物的比较。
单次口服 55P0251 可改善小鼠的葡萄糖耐量，其 ED 在 1.5 和 2mg/kg 之间（曲线下面积减少，1mg/kg 减少-18%；5mg/kg 减少-30%；27mg/kg 减少-47%）。药代动力学研究显示出有吸引力的特性，包括在大鼠中的血浆半衰期约为 3 小时和生物利用度约为 58%。55P0251 增强了分离的小鼠胰岛的葡萄糖刺激的胰岛素释放，并通过增加大鼠的胰岛素分泌改善了葡萄糖耐量（胰岛素曲线下面积增加+184%）。与磺酰脲类和格列奈类不同，55P0251 在基础条件下几乎不刺激胰岛素释放，也不会在体内引起低血糖，但它增强了对葡萄糖和其他胰岛素刺激物（KCl、胰高血糖素样肽-1）的分泌反应。与现有的抗糖尿病药物进行比较，并检查与分子靶点（K 通道、二肽基肽酶-4、胰高血糖素样肽-1 受体）的相互作用，排除了目前市场上药物针对的分子机制。
55P0251 是一种新型化合物，通过增强葡萄糖刺激的胰岛素释放，有力地对抗啮齿动物的高血糖症。
