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  • Type II diabetes is characterized by


    Type II diabetes is characterized by an inability to maintain glucose homeostasis due to insulin desensitization and/or insufficient insulin secretion. GPR40, also known as free fatty sevelamer hcl mg receptor 1 (FFAR1), is a member of the G-protein-coupled lipid-activated family of receptors and is primarily expressed in pancreatic beta cells and intestinal enteroendocrine cells, and to a lesser extent the brain. When activated by its endogenous ligands (medium and long chain fatty acids) GPR40 elicits increased insulin secretion from islet β-cells only in the presence of elevated glucose levels. This unique mechanism to treat type II diabetes has the potential to mitigate the risk of hypoglycemia seen with other insulin secretagogues and has triggered significant efforts at identifying therapeutic agents utilizing this target. Clinical candidates targeting GPR40 as a means to treat diabetes have been reported in the literature, , , and have been solely represented by orthosteric agonists such as TAK-875 () that partially activate the receptor. This direct binding to the orthosteric domain has been shown to have provided clinical proof of concept for the mechanism by lowering HbA1c through GPR40-mediated insulin secretion. TAK-875, the most clinically advanced GPR40 partial orthosteric agonist, was terminated in Phase III due to concerns about liver toxicity. Lipophilic carboxylic acid such as TAK-875 readily form acyl glucuronides in vivo, which may give rise to reactive metabolites that contribute toward the observed DILI signal., Recently, a different approach to the utilization of GPR40 mediated insulin secretion as a therapeutic target had been initially reported by researchers at Amgen, , and Bristol-Myers-Squibb wherein they described GPR40 full agonists whose mode of action is via positive allosteric modulation (effectively AgoPAMs), on orthosteric ligands (e.g. DHA). Further evidence of the proposed mode of action of AgoPAMs was recently disclosed where we showed cooperative allostery of AgoPAMs by simultaneously co-crystallizing a full orthosteric agonist and an AgoPAM within the GPR40 receptor. In addition to stimulating insulin secretion via pancreatic action, GPR40 AgoPAMs are known to stimulate GLP-1 secretion in the gut, potentially accounting for the observed enhancement in efficacy. Moreover, we have recently reported the discovery of a novel class of biaryl chromans, i.e. compound , that operate as selective GPR40 AgoPAMs which demonstrated superior on-target in-vivo glucose lowering efficacy over GPR40 partial orthosteric agonists TAK-875 with no sign of tachyphylaxis in a 2-week in-vivo study.
    Introduction G protein-coupled receptors (GPCRs), the largest and most versatile class of membrane receptors in eukaryotes, represent the most common target of modern therapeutic drugs. They broadly participate in physiological processes and pathophysiological conditions through coupling to specific G protein families (Gαs, Gαi/o, Gαq/11 and others), which in turn trigger the production of second messengers such as cAMP, inositol phosphates and Ca2+ to regulate different intracellular signaling pathways [1,2]. G protein-coupled receptor 40 (GPR40), also known as free fatty acid receptor 1 (FFAR1), belongs to rhodopsin-like GPCR family and demonstrated to be highly expressed in pancreatic β-cells and gastrointestinal enteroendocrine cells. Activation of this receptor by either endogenous long-chain free fatty acids or small-molecule agonists can promote glucose-stimulated insulin secretion (GSIS) by not only directly acting on β-cells but also indirectly through regulation of incretin secretion [3]. Considering that GPR40 only stimulate insulin release in the presence of elevated glucose levels, it has drawn considerable attention from both academia and industry as a novel target for the treatment of type 2 diabetes (T2D) with minimal risk of iatrogenic hypoglycemia [4,5]. As shown in Fig. 1, a variety of synthetic small-molecule GPR40 agonists have been reported based on the 3-phenylpropanoic acid scaffold. Among them, the most successful example was TAK-875 (fasiglifam), which exhibited potent agonist activity and high selectivity towards GPR40 and was advanced into clinical studies as an oral active drug candidate. Treatment with TAK-875 led to improved insulin secretion in T2D patients with a sharp reduction in glucose levels, including an average reduction in glycated haemoglobin (HbA1C) of 1.2%. At the 50 mg dose used in phase 3 clinical trials, TAK-875 primarily demonstrated improvement on fasting plasma glucose levels with increased insulin secretion observed [6]. However, by the end of 2013, Takeda voluntarily decided to terminate the development activities for TAK-875 in phase 3 clinical studies as this compound demonstrated clear signs of liver toxicity in patients. Although it was still unclear whether the hepatotoxicity of TAK-875 was a molecule-specific issue or a target-related issue, a recent study indicated that TAK-875 may affect bile acid and bilirubin homeostasis through inhibiting the efflux transporter and uptake transporters, and therefore produced off-target effects in the liver [7]. Given that the failure of TAK-875 was most likely a molecule-specific issue and GPR40 played a vital role in regulating glucose homeostasis, there was every expectation that some other GPR40 agonists might find their way into future clinical trials as anti-diabetic therapeutics (see Table 1).