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  • br Author contributions br Conflict of interests br Acknowle

    2022-01-27


    Author contributions
    Conflict of interests
    Acknowledgements This work was supported by NIH grant DK098730 to NHM.
    Free fatty acids play important roles in biological processes contributing to both health and disease. As essential nutritional components, free fatty acids are utilized as building blocks for energy storage and cell membrane integrity and as substrates for critical cellular pathways (i.e. Randle cycle). In addition to these roles, free fatty acids have been recognized as important signaling molecules involved in a variety of physiological processes including inflammation and insulin resistance and hence contribute to the pathologies of type 2 diabetes and obesity. Recently, numerous G-protein coupled receptors (GPCRs) have been identified that are activated by free fatty acids., , , , The GPCRs can be grouped according to the carbon chain length (short chain: <6 carbons; medium chain: 6–12 carbons; long chain: >12 carbons) and level of unsaturation of the fatty acids which activate the receptors, with free fatty PF-4708671 receptor 2 (FFA2/GPR43) and free fatty acid receptor 3 (FFA3/GPR41) activated by short chain fatty acids, G-protein coupled receptor 84 (GPR84) activated by medium chain fatty acids, free fatty acid receptor 1 (FFA1/GPR40) activated by saturated and unsaturated long-chain fatty acids, and free fatty acid receptor 4 (FFA4/GPR120) activated by unsaturated long-chain fatty acids including omega-3 fatty acids (ω-3 FAs)., Our interest in understanding the physiological processes governed by the long-chain fatty acid receptors led us to further consider FFA1 and FFA4 as candidates for small molecule drug discovery efforts. Previous reports have highlighted our group’s efforts leading to the identification of the FFA1 biased agonist GW9508 (∼100-fold selective for FFA1 over FFA4)., These studies provided the first evidence that small molecule mediated FFA1 agonism could be utilized for the pharmacological regulation of insulin secretion. FFA1 is expressed highest in the pancreas, with insulin secreting β-cells abundantly expressing the receptor, and has also been shown to also be present in intestine and brain., FFA1 amplified glucose-stimulated insulin secretion has been extensively studied and provides the basis for the current interest in FFA1 selective small molecule agonists for the treatment of type 2 diabetes., , , , FFA4 has been less extensively studied but numerous recent reports highlight the receptor in several pathologies associated with type 2 diabetes and the components of metabolic syndrome., , , FFA4 is abundantly expressed in several tissues including the intestine, adipose, and lung and is present in a variety of cell types including proinflammatory macrophages, intestinal L- and K-cells,, the mouse enteroendocrine STC-1 cell line, and in the taste buds of the tongue. This pattern of expression is consistent with the nutrient sensing and anti-inflammatory roles that have been reported for FFA4., , , Indeed, seminal studies aimed at identifying the receptors involved in nutrient stimulated glucagon-like peptide-1 (GLP-1) secretion have identified FFA4 as a candidate GPCR involved in long-chain fatty acid stimulated GLP-1 secretion. In addition the anti-inflammatory and insulin sensitizing effects of the ω-3 fatty acids DHA and EPA have been reported to occur through FFA4., , , Further understanding of the therapeutic potential of FFA4 activation would be greatly aided by the identification of small molecule agonists with good pharmacokinetic properties., , , , , , , With this goal in mind, efforts directed toward the identification of small molecule FFA4 agonists culminating in identification of phenylpropanoic acid agonists with pharmacokinetic properties appropriate for in vivo studies are described herein. Compound was identified as starting point for optimization following a cross-screening effort of our FFA1 program compounds (). The potency and efficacy of compound was determined using a ten-point dose response curve in mammalian U2OS cells transiently expressing either human FFA1 or FFA4 using a FLIPR readout. The data revealed that compound was 17-fold selective for FFA1 over FFA4. Thus, a primary goal of this exercise was to explore the SAR against both receptors while identifying compounds with selectivity for the FFA4 receptor.