Improving Metabolic Stability with Deuterium: The Discovery of GPU-028, a Potent Free Fatty Acid Receptor 4 Agonists

Publication date: Available online 31 October 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Zheng Li, Xue Xu, Gang Li, Xiaoting Fu, Yanzhi Liu, Yufeng Feng, Mingyan Wang, Yunting Ouyang, Jing Han
The free fatty acid receptor 4 (FFA4) has emerged as a promising anti-diabetic target due to its function in improvement of insulin secretion and insulin resistance. The FFA4 agonist TUG-891 revealed great potential as a widely used pharmacological tool, but it has been suffered from high plasma clearance probably because the phenylpropanoic acid is vulnerable to β-oxidation. To identify metabolically stable analog without influence on physiological mechanism of TUG-891, we tried to incorporate deuterium at the α-position of phenylpropionic acid to afford compound 4 (GPU-028). As expected, GPU-028 revealed a longer half-life (T1/2 = 1.66 h), lower clearance (CL = 0.97 L/h/kg) and higher maximum plasma concentration (Cmax = 2035.23 μg/L), resulting in a 4-fold higher exposure than TUG-891. Although GPU-028 exhibited a similar agonistic activity in comparison to TUG-891, the hypoglycemic effect of GPU-028 was better than that of TUG-891 after treatment over four weeks in diet-induced obese mice. These positive results indicated that GPU-028 might be a better pharmacological tool than TUG-891 to explore physiological function of FFA4, especially on the in vivo study.

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