Discovery of MK-8282 as a Potent G-Protein-Coupled Receptor 119 Agonist for the Treatment of Type 2 Diabetes.,ACS Medicinal Chemistry Letters

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Discovery of MK-8282 as a Potent G-Protein-Coupled Receptor 119 Agonist for the Treatment of Type 2 Diabetes.
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2018-04-10 , DOI: 10.1021/acsmedchemlett.8b00073
Santhosh F Neelamkavil ₁ , Andrew W Stamford ₁ , Timothy Kowalski ₁ , Dipshikha Biswas ₁ , Craig Boyle ₁ , Samuel Chackalamannil ₁ , Yan Xia ₁ , Charles Jayne ₁ , Bernard Neustadt ₁ , Jinsong Hao ₁ , Hong Liu ₁ , Xing Dai ₁ , Hana Baker ₁ , Brian Hawes ₁ , Kim O'Neill ₁ , Huadong Tang ₁ , William J Greenlee ₁

Affiliation

The ever-growing prevalence of type 2 diabetes in the world has necessitated an urgent need for multiple orally effective agents that can regulate glucose homeostasis with a concurrent reduction in body weight. G-Protein coupled receptor 119 (GPR119) is a GPCR target at which agonists have demonstrated glucose-dependent insulin secretion and shows beneficial effects on glycemic control. Herein, we describe our efforts leading to the identification of a potent, oral GPR-119 agonist, MK-8282, which shows improved glucose tolerance in multiple animal models and has excellent off-target profile. The key design elements in the compounds involved a combination of a fluoro-pyrimidine and a conformationally constrained bridged piperidine to impart good potency and efficacy.

中文翻译：

发现 MK-8282 作为一种有效的 G 蛋白偶联受体 119 激动剂，用于治疗 2 型糖尿病。

世界上 2 型糖尿病的患病率不断上升，迫切需要多种口服有效药物来调节葡萄糖稳态，同时减轻体重。 G 蛋白偶联受体 119 (GPR119) 是 GPCR 靶点，激动剂已证明其葡萄糖依赖性胰岛素分泌，并对血糖控制显示出有益作用。在此，我们描述了我们在鉴定一种有效的口服 GPR-119 激动剂 MK-8282 方面所做的努力，该激动剂在多种动物模型中显示出改善的葡萄糖耐量，并具有出色的脱靶特征。这些化合物的关键设计元素涉及氟嘧啶和构象受限的桥联哌啶的组合，以赋予良好的效力和功效。

更新日期：2018-04-10

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