含酰胺连接基的 GPR40 激动剂的设计、合成及构效关系研究。
Design, synthesis and structure-activity relationship studies of GPR40 agonists containing amide linker.
机构信息
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
出版信息
Eur J Med Chem. 2018 May 25;152:175-194. doi: 10.1016/j.ejmech.2018.04.023. Epub 2018 Apr 20.
Free fatty acid receptor 1 (FFAR1/GPR40) attracted significant attention as a potential target for developing novel antidiabetic drugs because of its unique mechanism in glucose homeostasis. Several reports have expressed concerns about central nervous system (CNS) penetration of GPR40 agonists, which is possibly attributed to their high lipophilicity and low total polar surface area. Herein, we report our efforts to improve the physicochemical properties and pharmacokinetic profiles of LY2881835, a GPR40 agonist that had undergone Phase I clinical trial, through a series of structural optimizations. We identified an orally efficacious compound, 15k, which possessed increased plasma exposure, prolonged half-life and reduced CNS exposure and liver to plasma distribution ratio compared with LY2881835. 15k is a potentially valuable lead compound in the development of safe and efficacious GPR40-targeted drugs to treat type 2 diabetes mellitus.
游离脂肪酸受体 1（FFAR1/GPR40）因其在葡萄糖稳态中的独特作用机制，成为开发新型抗糖尿病药物的一个有吸引力的靶点。有几项报道对 GPR40 激动剂的中枢神经系统（CNS）穿透性表示担忧，这可能归因于它们的高亲脂性和低总极性表面积。在此，我们报告了通过一系列结构优化，来改善已经进行 I 期临床试验的 GPR40 激动剂 LY2881835 的理化性质和药代动力学特征的努力。我们确定了一种具有口服疗效的化合物 15k，与 LY2881835 相比，它具有更高的血浆暴露量、更长的半衰期以及更低的 CNS 暴露量和肝脏与血浆的分布比。15k 是开发安全有效的 GPR40 靶向药物治疗 2 型糖尿病的有价值的潜在先导化合物。
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