Clinical data showed TAK was rapidly absorbed with a

Clinical data showed TAK-875 was rapidly absorbed with a half-life of 28-30h and clearance primarily through glucouronidation in the liver with minimal urinary clearance [30]. TAK-875 made the glycosylated hemoglobin (HbA1c) levels fall significantly from baseline after 24-week administration in once daily dose of 25 and 50mg, respectively, which was similar to glimepiride [31]. Although TAK-875 demonstrated promising therapeutic effect, Takeda decided to withdraw its clinical trials, due to concerns about liver toxicity. Whether the hepatotoxicity was molecule-specific or mechanism related is not clear. Recent study indicated that TAK-875 inhibited hepatobiliary transporters such as multidrug resistance-associated protein 2 and organic anion transporter protein, affecting bile m1 receptor and bilirubin homeostasis, which might contribute to hyperbilirubinemia and cholestatic hepatotoxicity [32]. Similar to the structure of Takeda series, the molecules acting on GPR40 with an oxetanyl group at the β-position was claimed in the patent application by Piramal, which exhibited good efficacy in an inositol-triphosphate accumulation assay (exemplified by 4, Fig. 6) [33]. Among them, P11187 as a treatment for T2D has entered phase I clinical trials in US, whose chemical structure was not disclosed [34]. LY2881835 was a potent GPR40 agonist (EC50=233nM) developed by Eli Lilly company (Fig. 7), which was thoroughly characterized in vitro and in vivo. The spiropiperidine compounds provided desired selective activation of GPR40 without detectible PPAR activity [35]. The compound also displayed a dose dependent reduction of blood glucose and a remarkable increase in insulin secretion during OGTT and IPGTT. In 2011, Eli Lilly initiated a phase I clinical trial in the US which was completed in August 2011. However clinically significant adverse effects were observed and no further development has been reported. In 2013, a novel polar derivative with 1-(thiophen-2-ylmethyl)-1,2,3,4-tetrahydroquinoline as the aromatic fragment (5, Fig. 7) was claimed by Eli Lilly in patent application, displaying an EC50 of 152nM and 84% maximal efficacy when examined in calcium flux primary assay [36]. This compound exhibited potent glucose lowering effect (ED50=1.0mg/kg, based on AUCs) and its activation on GPR40 led to in vivo antidiabetic efficacy. Further structurally modified analogs with polar triazole-pyridine moiety were patented, too (6–7, Fig. 7). Among them, compound 6 had an EC50 of 119nM and 76% maximal efficacy [37], [38]. The ED90 for glucose lowering effect on day 1 was 4.1mg/kg and on day 21 was 5.0mg/kg. So GPR40 was not desensitized following 21days of oral administration with this compound. In 2012, Connexios published one patent on GPR40 agonists, where the oxime functionality containing chemical structure was claimed (Fig. 8). Most of this series compounds, e.g.8 possessed EC50<10nM [39]. In 2013, Connexios reported the therapeutic potential of CNX-011-67, a highly potent GPR40 agonist (EC50=0.24nM), whose chemical structure was not disclosed yet. In this study, the robust control of both the onset and progress of hyperglycemia was achieved in the male ZDF rats after treatment with CNX-011-67 for 7weeks [40]. It can enhance glucose mediated insulin secretion, improve the glucose sensitivity of beta cells, increase insulin content and reduce beta cell apoptosis [40]. Recently, China Pharmaceutical University reported their structural modification on Takeda series by incorporating the oxygen atom into the β-position to avoid β oxidation (9–10, Fig. 9) [41]. They also tried to employ glycine as the linker to decrease the molecular weight and lipophilicity (10, Fig. 9) [42]. Further structural optimization was focused on the replacement of the terminal phenyl group with polar heteroaromatic rings such as pyrrol, 3,5-dimethl isoxazole and thiazole (11–13, Fig. 9) to remove the biphenyl moiety, which was verified crucial for the toxicity by the researchers of Daiichi Sankyo [43], [44], [45]. Compound 13 showed robust hypoglycemic effect and low liver toxicity [45].