Discovery of 2-Pyridylpyrimidines as the First Orally Bioavailable GPR39 Agonists

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• 作者：Stefan Peukert ; Richard Hughes ; Jill Nunez ; Guo He ; Zhao Yan ; Rishi Jain ; Luis Llamas ; Sarah Luchansky ; Adam Carlson ; Guiqing Liang ; Vidya Kunjathoor ; Mike Pietropaolo ; Jeffrey Shapiro ; Anja Castellana ; Xiaoping Wu ; Avirup Bose
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2014
• 出版时间：October 9, 2014
• 年：2014
• 卷：5
• 期：10
• 页码：1114-1118
• 全文大小：300K
• ISSN：1948-5875

文摘

The identification of highly potent and orally bioavailable GPR39 agonists is reported. Compound 1, found in a phenotypic screening campaign, was transformed into compound 2 with good activity on both the rat and human GPR39 receptor. This compound was further optimized to improve ligand efficiency and pharmacokinetic properties to yield GPR39 agonists for the potential oral treatment of type 2 diabetes. Thus, compound 3 is the first potent GPR39 agonist (EC₅₀s 鈮?1 nM for human and rat receptor) that is orally bioavailable in mice and robustly induced acute GLP-1 levels.

Keywords:

GPR39 agonists; GPR39 receptor; Zn²⁺-sensing receptor; antidiabetic treatment; 尾-cell protection; GLP-1 secretion; insulin secretion