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    Recently, there are only a spot of FFA4 agonists reported in the literature (Fig. 1),13, 14, 15 and there is no selective FFA4 agonists have reached clinical trial for the treatment of T2DM. TUG-891, the first potent and selective FFA4 agonist, was developed in University of Southern Denmark as a widely used pharmacological tool to explore the physiological function of FFA4.16, 17, 18, 19 However, TUG-891 has been suffered from high plasma clearance (CL = 3.67 L/h/kg) in rats probably because the phenylpropanoic Ro3280 is vulnerable to β-oxidation just as the previous reported FFA1 agonists with phenylpropanoic acid moiety.20, 21 In the pathway of β-oxidation (Fig. 2), the cinnamic acid 2 was initially formed by dehydrogenation and ultimately obtained benzoic acid 3. There are many classic strategies including α- and/or β-disubstitution were widely used to block the metabolic hotspots. Meanwhile, a perfect strategy with improved metabolic stability was also expected to have little or no impact on the physiological mechanism of TUG-891 due to its robustly pharmacodynamic performance in vitro. Therefore, we tried to improve metabolic stability by incorporating α-position deuterium afforded compound 4 (GPU-028, Fig. 2), because the kinetic isotope effect of deuterium at sites of metabolism is the rate determining step can reduce metabolism.23, 24, 25 Moreover, the incorporation of deuterium may have little effect on the physiological mechanism of TUG-891 attributed to the small differences between hydrogen and deuterium. As expected, GPU-028 revealed a similar agonistic activity and better selectivity in comparison to TUG-891. Besides, GPU-028 exhibited lower clearance, higher maximum concentration, and longer half-life than TUG-891. Although in vitro activity difference between TUG-891 and GPU-028 is quite small, the glucose-lowering effect of GPU-028 was better than that of TUG-891 during a chronic treatment study in diet-induced obese (DIO) mice.
    Results and discussion
    Experimental section
    Acknowledgements This work is supported by the National Natural Science Foundation of China (81602964), and the Natural Science Foundation of Jiangsu Province (BK20150243).
    Introduction Type 2 diabetes mellitus (T2DM), a most common type of diabetes, is characterized by impaired insulin secretion and/or sensitization.1, 2 Various available oral insulin secretagogues, such as sulfonylureas, are widely used for the treatment of T2DM. However, these available therapies are often related to side effect of hypoglycemia because insulin secretion induced by them are independent of glucose. Thus, there are unmet needs for new oral insulin secretagogues without the risk of hypoglycemia. The free fatty acid receptor 1 (FFA1, or GPR40), has emerged as an attractive target in the last decade for the treatment of T2DM. FFA1 is predominantly expressed in the pancreatic β-cell and augments insulin secretion dependent on the levels of glucose, providing a huge advantage of reducing incidence rate of hypoglycemia.6, 7, 8 Moreover, the limited tissue distribution of FFA1 suggests that less possibilities of adverse effects related to FFA1 in other tissues. As summarized in the most recent review, many literatures have reported structurally diverse FFA1 agonists based on arylalkanoic acids (Fig. 1),11, 12, 13, 14, 15, 16, 17, 18 and the clinical trials were performed to evaluate the potential of TAK-875, LY2881835 and AMG-837 as anti-diabetic agents.5, 10 In addition, the chemical space of FFA1 agonists with different scaffolds has also been explored by our colleagues.17, 18, 19, 20, 21, 22, 23, 24 In particular, the common biphenyl scaffold has been systematically replaced by various heterocycles in our laboratory (eg., compounds 1 and 2 in Fig. 1) to reduce the lipophilicity, and the lipophilicity of candidate is usually related to a higher promiscuity, metabolic instability, and failure rates in research and development.25, 26, 27, 28, 29 Herein, we describe our efforts toward discovering preferable heterocycle scaffold with better drug-like physicochemical properties directed by lipophilicity, ligand efficiency (LE) and ligand lipophilicity efficiency (LLE) (Fig. 2). These efforts ultimately led to the identification of compound 11, a potent agonist with improved physicochemical properties and excellent pharmacokinetic (PK) profiles.