LY3298176,一种新颖的双GIP和GLP-1受体激动剂治疗2型糖尿病:从发现到临床的概念。

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Coskun T,单桅帆船千瓦,Loghin C, Alsina-Fernandez J, Urva年代,Bokvist KB,崔X, Briere哒,卡布瑞拉啊,Roell WC, Kuchibhotla U·莫耶斯说JS,本森CT,希梅诺再保险公司D 'Alessio哒,Haupt

LY3298176,一种新颖的双GIP和GLP-1受体激动剂治疗2型糖尿病:从发现到临床的概念。

摩尔金属底座。2018年12月,18:3-14。doi: 10.1016 / j.molmet.2018.09.009。Epub 2018年10月3。

PubMed ID
30473097 (在PubMed
]
文摘

目的:一种新型双GIP和GLP-1受体激动剂,LY3298176,开发确定GIP的代谢作用增加了选择性的建立临床益处glp - 1在2型糖尿病受体受体激动剂(2型糖尿病)。方法:LY3298176是脂肪酸改性肽双GIP和GLP-1受体激动剂活动为每周皮下管理而设计的。LY3298176体外特征,使用信号和功能化验细胞系表达重组或内源性肠促胰岛素受体,并使用体重,体内食物的摄入量,胰岛素分泌和小鼠的血糖的概要文件。第一阶段,随机,安慰剂对照,双盲研究是由三部分组成:single-ascending剂量(悲伤;0.25 8毫克剂量)和四周multiple-ascending剂量(疯了;0.5剂量-10毫克)在健康受试者的研究(HS),紧随其后的是一个四周multiple-dose阶段1 b概念验证(POC;0.5剂量-15毫克)患者2型糖尿病(ClinicalTrials.gov没有。NCT02759107)。高于5毫克剂量被滴定法获得,dulaglutide (DU)作为一个积极的控制。的主要目标是调查LY3298176的安全性和耐受性。 RESULTS: LY3298176 activated both GIP and GLP-1 receptor signaling in vitro and showed glucose-dependent insulin secretion and improved glucose tolerance by acting on both GIP and GLP-1 receptors in mice. With chronic administration to mice, LY3298176 potently decreased body weight and food intake; these effects were significantly greater than the effects of a GLP-1 receptor agonist. A total of 142 human subjects received at least 1 dose of LY3298176, dulaglutide, or placebo. The PK profile of LY3298176 was investigated over a wide dose range (0.25-15 mg) and supports once-weekly administration. In the Phase 1 b trial of diabetic subjects, LY3298176 doses of 10 mg and 15 mg significantly reduced fasting serum glucose compared to placebo (least square mean [LSM] difference [95% CI]: -49.12 mg/dL [-78.14, -20.12] and -43.15 mg/dL [-73.06, -13.21], respectively). Reductions in body weight were significantly greater with the LY3298176 1.5 mg, 4.5 mg and 10 mg doses versus placebo in MAD HS (LSM difference [95% CI]: -1.75 kg [-3.38, -0.12], -5.09 kg [-6.72, -3.46] and -4.61 kg [-6.21, -3.01], respectively) and doses of 10 mg and 15 mg had a relevant effect in T2DM patients (LSM difference [95% CI]: -2.62 kg [-3.79, -1.45] and -2.07 kg [-3.25, -0.88], respectively. The most frequent side effects reported with LY3298176 were gastrointestinal (vomiting, nausea, decreased appetite, diarrhoea, and abdominal distension) in both HS and patients with T2DM; all were dose-dependent and considered mild to moderate in severity. CONCLUSIONS: Based on these results, the pharmacology of LY3298176 translates from preclinical to clinical studies. LY3298176 has the potential to deliver clinically meaningful improvement in glycaemic control and body weight. The data warrant further clinical evaluation of LY3298176 for the treatment of T2DM and potentially obesity.

beplay体育安全吗DrugBank数据引用了这篇文章

药物
药物靶点
药物 目标 类 生物 药理作用 行动
Tirzepatide 肠抑胃肽 蛋白质 人类
是的
受体激动剂
 细节
Tirzepatide Glucagon-like肽受体1 蛋白质 人类
是的
受体激动剂
 细节
药物载体
药物 航空公司 类 生物 药理作用 行动
Tirzepatide 血清白蛋白 蛋白质 人类
未知的
粘结剂
 细节