The free fatty acid receptor 1 (FFA1) is a potential target due to its function in enhancing of glucose‐stimulated insulin secretion. The FFA1 agonist GW9508 has great potential for the treatment of type 2 diabetes mellitus, but it has been suffering from high plasma clearance probably because the phenylpropanoic acid is vulnerable to β‐oxidation. To identify orally available analog without influence on the unique pharmacological mechanism of GW9508, we tried to interdict the metabolically labile group by incorporating two deuterium atoms at the α‐position of phenylpropionic acid affording compound 4 (HWL‐066). As expected, HWL‐066 revealed a lower clearance (CL = 0.23 L−1 hr−1 kg−1), higher maximum concentration (Cmax = 5907.47 μg/L), and longer half‐life (T1/2 = 3.50 hr), resulting in a 2.8‐fold higher exposure than GW9508. Moreover, the glucose‐lowering effect of HWL‐066 was far better than that of GW9508 and comparable with TAK‐875. Different from glibenclamide, no side‐effect of hypoglycemia was observed in mice after oral administrating HWL‐066 (80 mg/kg).
