The free fatty acid receptor 1 (FFA1) is a potential target due to its function in enhancement of glucose-stimulated insulin secretion. Takeda’s compound 1 has robustly in vitro activity for FFA1, but it has been suffered from poor pharmacokinetic (PK) profiles because the phenylpropanoic acid is vulnerable to β-oxidation. To identify orally available agonists, we tried to interdict the metabolically labile group by incorporating two deuterium atoms at the α-position of phenylpropionic acid. Interestingly, the differences of physicochemical properties between hydrogen and deuterium are quite small, but there are many differences in the structure-activity relationship between phenylpropionic acid series and present deuterated series. Further optimizations of deuterated series led to the discovery of compound 18, which exhibited a superior balance in terms of in vitro activity, lipophilicity, and solubility. Better still, compound 18 revealed a lower clearance (CL = 0.44 L/h/kg), higher maximum concentration (C_max = 7584.27 μg/L), and longer half-life (T_1/2 = 4.16 h), resulting in a >23-fold exposure than compound 1. In subsequent in vivo pharmacodynamic studies, compound 18 showed a robustly glucose-lowering effect in rodent without the risk of hypoglycemia.

游离脂肪酸受体1（FFA1）由于其在增强葡萄糖刺激的胰岛素分泌中的作用而成为潜在的靶标。武田的化合物1具有强大的体外FFA1具有FFA1活性，但由于苯丙酸易受β-氧化作用，因此它的药代动力学（PK）曲线较差。为了鉴定口服可用的激动剂，我们试图通过在苯丙酸的α-位引入两个氘原子来阻断代谢不稳定的基团。有趣的是，氢和氘之间的理化性质差异很小，但苯基丙酸系列与目前的氘代系列之间在构效关系上存在许多差异。氘代系列的进一步优化导致发现化合物18，该化合物在体外活性，亲脂性和溶解性方面表现出优异的平衡。更好的化合物18揭示了较低的清除率（CL = 0.44 L / h / kg），较高的最大浓度（C _max  = 7584.27μg/ L）和较长的半衰期（T _1/2  = 4.16 h），导致> 23倍接触比化合物1大。在随后的体内药效学研究中，化合物18在啮齿类动物中显示出强烈的降糖作用，而没有低血糖的风险。