However the clinical development of

However, the clinical development of was terminated in 2013 due to the concerns over liver toxicity, raising important questions regarding the long-term safety and viability of targeting GPR40 and, more specifically, about our understanding of the pharmacobiology and signaling spectrum of this receptor. The molecular basis of the hepatotoxic effect was still unclear, yet GPR40 does not appear to be expressed in the liver , , suggesting that it is probably not related to the direct activation of GPR40, but might occur along the signaling cascade downstream of -triggered GPR40 activation pathway. Furthermore, the substantial improvement for T2DM without the risk of hypoglycemia by GPR40 agonists in clinical trials still holds a big promise for GPR40 as the target of a novel class of insulin secretagogues. The pharmaceutical society keeps enthusiastic for the pursue of chemically and structurally diverse GPR40 agonists with high safety to address these concerns and give new insights into the receptor’s basic biology and physiological role. In particular, the recently published crystal structure of GPR40 in complex with and the discovery of multiple putative ligand binding sites may guide the design of bitopic ligand with improved target affinity and/or selectivity, opening an interesting avenue for GPR40-based pharmacotherapeutics. Herein we will review the latest progress on the understanding of the biology and pharmacology of GPR40, and the medicinal chemistry efforts to evolve GPR40 agonists as safe and effective treatment for T2DM (2010–2016), especially focused on the unique pharmacobiology and structural optimization to improve the efficacy, safety and drug-likeness of the drug candidates targeting GPR40. The biological space of GPR40 agonists GPR40 (also known as free fatty RO4987655 sale 1 receptor, FFA1), a seven-transmembrane domain receptor, is predominantly expressed on pancreatic β-cells and enteroendocrine cells [5], [6]. Although GPR40 is also reported to be expressed in the brain, its function and mechanism is unclear yet [9]. GPR40 is activated by the endogenous ligands, i.e. medium to long-chain free fatty acids such as decanoic acid, linoleic acid (LA), docosahexaenoic acid (DHA) which are known potent agonists [6]. In these fatty acids the carboxyl functional group is essential for the activity. Several classes of small molecule GPR40 agonists have been identified with different biological characteristics. According to the measurement of Ca2+ reflux inducing insulin secretion compared to DHA and γ-LA, the synthetic GPR40 agonists can be divided into partial agonists and full agonists. Most of the current GPR40 agonists reported in the literature belong to partial agonists (e.g. TAK-875[10], AMG 837[11]). Recent findings suggest that full agonism of the receptor could, in addition to stimulating insulin release, engage the enteroinsular axis. Exemplified by AM 1638[12] and AM 5262[13], developed by Amgen, GPR40 full agonists not only showed superior in vivo efficacy to the partial agonist (i.e. AM 837), but also offered the significant advantage of stimulating incretin secretion (GLP-1 and GIP) through activation of GPR40 expressed on enteroendocrine cells, further incorporating the beneficial effects of GLP-1-based therapies (including enhanced satiety, cardioprotection, suppression of glucagon levels and weight loss) [13], [14], [15]. The insulinotropic signaling mechanism of GPR40 is only partially understood and shown in Fig. 1. Activation of the Gαq/11, the subunit of heterotrimeric G protein, by the endogenous ligands promotes the phospholipase C-mediated hydrolysis of phosphatidylinositol 4, 5-bisphosphate to form the inositol-triphosphate 3 (IP3) and diacylglycerol (DAG). Then IP3 binds to IP3 receptor on the endoplasmic reticulum to release Ca2+, while DAG activates the protein kinase D1 which promotes cortical F-actin remodeling and subsequent release of insulin [16]. Distinct from the endogenous ligands and synthetic partial GPR40 agonists which only signal through Gq, the insulin secretagogue mechanism of GPR40 full agonists engages both Gαq and Gαs signal pathways. Furthermore, recent study has shown that GPR40-mediated insulinotropic signaling can occur via a Gq/11-dependent pathway as well as a novel β-arrestin 2-dependent axis [17]. Further, these insulinotropic signaling axes are differentially engaged by different GPR40 ligands to promote insulin secretion, with the endogenous ligands PA and OA preferentially activating Gq/11 signaling and the synthetic ligand TAK-875 promoting β-arrestin 2-mediated signal transduction. Such biased agonism at GPR40 may instigate the development of new pathway selective GPR40 agonists endowing improved clinical efficacy and safety in T2DM (Fig. 1).