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

Peukert, Stefan and Hughes, Richard and Nunez, Jill and He, Guo and Yan , Zhao and Jain, Rishi and Llamas, Luis and Luchansky, Sarah and Carlson, Adam and Liang, Guiqing and Kunjathoor, Vidya and Pietropaolo, Michael and Shapiro, Jeffrey and Castellana, Anja and Wu, Xiaoping and Bose, Avirup (2014) Discovery of 2-Pyridylpyrimidines as the First Orally Bioavailable GPR39 Agonists. ACS MedChemLetters.


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 ≤ 1nM for human and rat receptor) that is orally bioavailable in mice and robustly induced acute GLP-1 levels.

Item Type: Article
Keywords: GPR39 agonists, b-cell protection, GLP-1 secretion, anti-diabetic treatment
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13


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