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    • Recently a lot of synthetic FFA agonists

    2021-10-08

    Recently, a lot of synthetic FFA1 agonists containing acidic moieties have been reported (Fig. 1) [13], [14], [15], [16], [17], [18], [19], [20], [21]. Notably, most of FFA1 agonists usually have the common biphenyl scaffold, which resulted in a relative deprivation in structure types of agonists [22], [23]. To enlarge the chemical space of FFA1 agonists, different structure scaffolds were introduced in our previous studies [24], [25], [26], [27], [28], [29], [30], [31], [32]. Currently, Srivastava et al. reported the co-crystal structure of FFA1 bound with TAK-875 (Fig. 2) [33]. Interestingly, the 1,3-dimethyl-5-(3-(methylsulphonyl)propoxy) benzene group of TAK-875 (left-hand of diphenyl scaffold) was exposed to the outside of receptor without direct interaction with FFA1. Therefore, we hypotheses the optimization of terminal benzene ring will further increase the interactions with the lateral residues such as Leu135, Val81 or Pro80. Herein, GW9508 (Fig. 1) was selected as lead compound due to its high-activity and unique non-biphenyl scaffold. However, the phenylpropanoic SR 1555 hydrochloride australia of GW9508 was susceptibility to β-oxidation, so the (2,3-dihydro-1-benzofuran-3-yl)acetic acid moiety of TAK-875 was introduced in this study (Fig. 3). Moreover, the function of FFA1 expressed in brain is unclear [10], and FFA1 agonist with low polar surface area (tPSA) exhibited obvious central nervous system (CNS) exposure [34]. Thus, the improvement of tPSA values is also an important design strategy to obtain drug-like lead compounds in this research. After exploration of series of non-biphenyl scaffolds, the potent lead compounds and their binding mode were identified.
    Results and discussion
    Conclusion In brief, inspired by the non-biphenyl agonist GW9508, we have structure-based designed a series of non-biphenyl scaffolds to further increase the interactions with the lateral residues at the outside of binding pocket. Moreover, the tPSA values were also monitored to guide the structure modification. These efforts ultimately led to the discovery of lead compounds 3 and 9, potent FFA1 agonists with two different non-biphenyl scaffolds, improved the tPSA values compared to GW9508. As expected, further induced-fit docking study suggested that compound 3 forms an edge-on interaction with the lateral residues Trp150, and compound 9 has additional hydrogen bond and δ-π interactions with residue Leu135, verifying our design strategy to increase interactions with the lateral residues. Furthermore, the lead compounds 3 and 9 have a great potential on suppressing the excursion of plasma glucose in mice. All of these results might help us to design more effective FFA1 agonists with non-biphenyl scaffolds.
    Experimental section
    Acknowledgements This study was supported by grants from the National Natural Science Foundation of China (Grants 81673299, 81273376 and 81320108029), and Guangdong Province Medical Science and Technology Research Fund (Grant A2018273).
    Introduction Type 2 diabetes mellitus (T2DM) is one of the fastest growing syndromes characterized by insufficient insulin secretion and/or insulin resistance.1, 2 The free fatty acid receptor family provides a goldmine of potent anti-diabetic targets, and the free fatty acid receptor 1 (FFA1) and free fatty acid receptor 4 (FFA4) are most closely associated with the regulatory pathways of T2DM. FFA1 is predominantly expressed in pancreatic β-cells and enhancing the insulin secretion in a glucose-dependent manner.4, 5 The FFA4, also known as GPR120, is mainly located in intestine, macrophages, and adipose tissue.6, 7, 8 FFA4 located in intestine can indirectly promoted insulin secretion by regulating the release of incretins such as GLP-1 and GIP.6, 9 In macrophages and adipose tissue, the activated FFA4 is involved in the improvement of insulin sensitization.7, 10 Therefore, FFA4 has emerged as a promising anti-diabetic target due to its potential for the improvement of insulin secretion and insulin resistance, two typical features for T2DM.11, 12