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  • br Conclusion In summary a series


    Conclusion In summary, a series of novel GPR40 agonists bearing phenylpropiolic ASP015K motif with favorable metabolic stability were prepared and evaluated for their activities as GPR40 agonists. Among them, compound 9 was identified as a structurally distinct GPR40 agonist possessing potent activity in vitro, and was effective in cellular insulin secretion in MIN6 cells under high-glucose conditions which could be reversed by a selective GPR40 antagonist GW1100. In vivo, compound 9 significantly lowered plasma glucose levels in normal mice during an oral glucose tolerance test suggesting that this compound served as a valuable research tool to explore the therapeutic utility of GPR40 agonists.
    Experimental section
    Type 2 diabetes mellitus (T2DM) is the most prevalent form of diabetes affecting over 300 million people worldwide and therefore constitutes a serious global health issue. T2DM is a polygenic syndrome with not only a hereditary component but also a environmental etiology. T2DM is caused by inadequate sensitivity of cells to the action of insulin and/or insufficient insulin production by pancreatic beta cells. Obesity is also a risk factor for T2DM. In most individuals, the pancreatic beta cells compensate for obesity-associated insulin resistance by expanding their functional mass and increasing the secretion of insulin. The failure of the beta cells to realize this compensation results in the development of T2DM in a subset of ca. 20% of obese individuals., The recent discovery of the G-protein-coupled receptor GPR40 with high expression levels in pancreatic beta cells and its ability to induce glucose-stimulated insulin secretion (GSIS) upon activation, sparked interest in GPR40 as a potential therapeutic target to enhance insulin secretion in type 2 diabetics. GPR40, also known as free fatty acid receptor 1 (FFAR1), is a member of the rhodopsin family of G-protein coupled receptors that were shown to be endogenously activated by medium- to long-chain saturated and unsaturated fatty acids (C) through receptor deorphanization studies., , At least three distinct binding sites have been identified on the GPR40 receptor with two types of synthetic agonists discovered based on their binding sites, ligand specificities and degree of intrinsic activity. GPR40 can signal through not only IP3 but also cAMP depending upon the type of agonist ligand used. A full agonist engages both signaling mechanisms in contrast to the endogenous long-chain fatty acid (LCFA) ligands and partial agonists. Thus, stimulation of GPR40 by endogenous LCFAs or by the synthetic partial agonists result in a rather limited incretin response and the consequential insulin secretion, whereas synthetic GPR40 full agonists stimulate robust GLP-1 and GIP responses in addition to the insulin secretion. These incretins, in turn, can also stimulate additional insulin secretion via binding to their own receptors on beta cells. Owing to this dual mechanism of action, leading to greater insulin secretion and potentially superior glycemic control, GPR40 full agonism may be preferable over partial agonism. Representative examples of currently known GPR40 full agonists are shown in . Amgen GPR40 full agonist was the very first GPR40 ligand reported to exhibit greater glucose lowering ability compared to the partial agonists., shows biaromatic GPR40 full agonists which are closely related in structure. The Amgen full agonist differs from the others due to the presence of a central benzenoid core structure. The Takeda and Janssen full agonists contain nitrogenous 6-membered heterocyclic central ring structures. However, when these different central ring structures were identically substituted, was the most potent compound in both human and rat GPR40 Ca assays, (). Our initial optimization work on the lead compound was focused on finding suitable replacements for the carboxylic acid function and the β-cyclopropyl side chain. The traditional medicinal chemistry approach of replacing the acid moiety with acid isosteres did not produce successful results. Additionally, the β -cyclopropyl side chain with the () configuration was also found to be optimal for the GPR40 full agonist activity of (data not shown). The SAR exploration around the 2- fluoro-5-methoxy phenyl ring revealed that it could be exchanged with 4-substituted 5-fluoro-2-methoxypyridine without a loss of potency compared to the parent compound ( vs ). However, the site that accommodates the dimethylcyclopentene moiety of the parent compound was found to be tolerant of a wide range of substituents (). The SAR exploration at this site encompassed the initial introduction of dissected fragments of dimethylcyclopentene followed by further modifications of the active substituents. Several large, lipophilic, structurally diverse substituents were tolerated at this site with improvement in GPR40 potency whereas hydrophilic groups negatively affected the activity of the compound (data not shown). The evaluation of many analogues finally led to the selection of as a compound of interest for further studies based on its favorable biological activity, early ADME and PK profile.