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 (T_1/2 = 1.66 h), lower clearance (CL = 0.97 L/h/kg) and higher maximum plasma concentration (C_max = 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.

游离脂肪酸受体4（FFA4）由于其在改善胰岛素分泌和胰岛素抵抗方面的作用而已成为有希望的抗糖尿病靶标。FFA4激动剂TUG-891具有广泛的药理作用，但其血浆清除率高，可能是因为苯丙酸易受β-氧化的困扰。为了鉴定代谢稳定的类似物而不影响TUG-891的生理机制，我们尝试将氘结合在苯丙酸的α-位上以提供化合物4（GPU-028）。如预期的那样，GPU-028显示出更长的半衰期（T _1/2  = 1.66 h），更低的清除率（CL = 0.97 L / h / kg）和更高的最大血浆浓度（C _max = 2035.23μg/ L），导致暴露量比TUG-891高4倍。尽管与TUG-891相比，GPU-028表现出相似的激动活性，但是在饮食诱导的肥胖小鼠中，经过4周的治疗后，GPU-028的降血糖作用优于TUG-891。这些积极的结果表明，GPU-028可能是比TUG-891更好的药理工具，以探索FFA4的生理功能，尤其是在体内研究中。