br Author contributions statement P N Y designed the study

Author contributions statement P.N.Y. designed the study, analyzed the data and prepared the draft of the manuscript. C.S performed the experiments, analyzed the data and generated Fig. 1, Fig. 2, Fig. 3, Fig. 4, Fig. 5, Fig. 6, Fig. 7, Fig. 8. A.K. and S.D. made Supplementary Figs. S1 and S2. D.U. helped in creating Fig. 3. All authors provided editorial assistance for this manuscript.
Competing financial interests
Acknowledgments The authors thank Bryan Roth from the University of North Carolina for kindly gifting the GPR40 and GPR120 tango plasmids used in this study. We also acknowledge Intravital Imaging Facility Olympus BX61-FV1200-MPE (supported by the MoES project and the THUNDER grant) and Leica Confocal Microscope facility in MSB. We thank Dr. Gilad Barnea (Brown University, USA) for providing HTLA cells. Furthermore, this work was supported by the Ramanujan Fellowship Grant (RJN-50/2011) to PNY (DST, Government of India), fellowships (JRF and SRF) to CS (CSIR, Government of India), (JRF and SRF) SD and AK (UGC, Government of India), and network grants THUNDER (BSC0102) and UNDO (BSC0103) from Council of Scientific and Industrial Research (CSIR). We also acknowledge Dr. Amogh A. Sahasrabuddhe for his help in acquiring confocal images and Mr. Aaram A Kumar and Mr. Ayush Kumar for editorial assistance. This manuscript bears CDRI communication number 9713.
Introduction Diabetes has become a serious worldwide health care problem in recent years. The International Diabetes Federation estimates that in 2017 >425 million people were living with diabetes. Type 2 diabetes mellitus (T2DM), representing 95% of all diabetes cases, is characterized by insufficient insulin secretion and insulin resistance which results in high blood glucose levels. Some of the available treatments for T2DM have been associated with undesired adverse effects such as gastrointestinal symptoms, weight gain, liver damage, and a high risk of hypoglycemia.2, 3 Therefore, there is an urgent need for preferable hypoglycemic drugs with improved safety.4, 5 G protein-coupled receptor 40 (GPR40), also known as FFA1 (free fatty pyrazine uses receptor 1) is primarily expressed in the β-cells of the pancreas and enteroendocrine cells. It is activated by medium- and long-chain free fatty acids, leading to the enhancement of glucose-stimulated insulin secretion only in the presence of elevated glucose levels. This characteristic makes this receptor an excellent antidiabetic drug target with little or no risk of hypoglycemia.6, 7 Considerable effort has been made to focus on the development of small molecule GPR40 agonists in the past few years (Fig. 1).8, 9, 10 TAK875 (compound 1), the most advanced compound from Takeda, validates this target as an effective approach for the treatment of T2DM in clinical trials.11, 12 Unfortunately, TAK875 was discontinued during phase III clinical trials due to liver-associated adverse events in patients. Because GPR40 is not expressed in the liver, the findings are unlikely to be a direct result of GPR40 agonism. It is speculated that the hepatotoxicity might be structure-related.15, 16 Therefore, it is an urgent mission for medicinal chemists to extend the chemical space and identify structurally distinct GPR40 agonists with improved liver safety. Several series of GPR40 agonists have already been published and we find that there is a common structural moiety of the benzyloxy fragment in these compounds.17, 18, 19, 20, 21, 22, 23, 24, 25 However, this may result in poor oral pharmacokinetic profiles (PK) and a potential safety concern due to the benzaldehyde fragment resulting from metabolic oxidation at the benzyl position.26, 27 In addition, the biphenyl structure of these compounds has been associated with cytotoxicity through the inhibition of mitochondrial respiratory chain complex 1 in reported literatures.28, 29 Therefore, as an effort to identify novel GPR40 agonists with improved PK properties and safety profiles, we designed a structurally distinct series of GPR40 agonists with the benzyloxy and biphenyl structure removed. In this novel skeleton, we introduced an ethylene glycol ether fragment instead of the benzyloxy group, and further constructed a fused-ring structure between the ortho-position of the left phenyl ring and ethylene glycol ether (Fig. 2). In this way, decreased molecular flexibility and less rotatable bonds may improve the physiochemical properties while preserving GPR40 agonistic potency.