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  • br Author contribution br Declaration of interest br Acknowl

    2022-05-13


    Author contribution
    Declaration of interest
    Acknowledgements This work was supported by National Natural Science Foundation of China (Grants 81473093) and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM1601ZZ-02).
    Introduction Diabetes represents a major health concern, especially in developing countries. According to the World Health Organization (WHO), more than 180 million people worldwide have diabetes and this number is expected to reach 366 million in 2030. Half of diabetes-related death cases occur in people under the age of 70 and this number is expected to increase by more than 50% in the next 10 years [1]. Moreover, the number of diabetic patients is continuously increasing due to several factors including population growth, increased life expectancy, increased rates of obesity, and lack of physical activity [2]. The most widely used antidiabetic medications are insulin secretagogues and insulin sensitizers. Examples of insulin secretagogues include sulfonylureas and meglitinides, while metformin and thiazolidinediones (TZDs) are insulin sensitizers. TZDs were introduced in the late 1990s as the first agents that control blood glucose level by acting on Peroxisome proliferator-activated receptors (PPARs) [3], [4], [5]. These represent a group of nuclear receptors that control cellular metabolism through the modulation of gene expression [6]. There are three distinct subtypes of PPARs: PPARα, PPARδ, and PPARγ. Activation of PPARγ has been shown to regulate glucose homeostasis, cellular differentiation, apoptosis, and inflammatory responses [7]. Over the past few years, there has been an influx of new antidiabetic agents acting on a variety of cellular targets. Free fatty Kif15-IN-2 mg receptors (FFARs) are a family of G-protein coupled receptors (GPCRs) that act as fatty acid sensors and play a crucial role in glucose homeostasis. Recent studies have demonstrated that both dietary fatty acids and synthetic agonists can stimulate glucose-dependent insulin secretion by acting on FFAR1 highly expressed in pancreatic β-cells [8], [9]. Several studies reported that modulation of PPARγ using TZDs was not efficient at controlling diabetes in some patients. This led to the use of combination therapies containing both insulin secreting and insulin sensitizing agents, such as Amaryl M® (glimepiride and metformin) and glucovance® (glibenclamide and metformin) [10]. These findings suggest the need for co-administration of insulin sensitizers and insulin secretagogues for the management of diabetes in some situations. Interestingly, it has been reported that some TZDs activate FFAR1 expressed in human HeLa cells with micromolar potency [11], [12]. In 2007, Owman and co-workers exploited the TZD scaffold for the design of FFAR1 ligands by combining fatty acids substructures with TZD heads. Two of the synthesized compounds in this study showed activity in the micromolar range (compounds A and B, Fig. 1) [13]. In a recent study, 2000 TZDs from the Merck compound collection were screened using the FLIPR assay in human GPR40-CHO cells. This led to the discovery of a partial agonist for GPR40 (compound C, Fig. 1) possessing an EC50 of 0.5 μM. The initial GPR40 activity of this compound was improved after subsequent optimization. However, it was inactive in binding assays against all human PPARα, -δ, and -γ isoforms [14]. The objective of this study is to design and synthesize drug-like molecules with agonistic activity on both receptors; PPARγ and FFAR1. These agents would act as insulin sensitizers and insulin secretagogues through their action on PPARγ and FFAR1, respectively. The design of drugs with dual mode of action is a valid approach. Aleglitazar, a PPAR modulator with affinity for both PPARα and PPARγ, is currently in phase III clinical trials [15]. Similarly, Asenapine, a dual antagonist of dopamine D2 and serotonin 5-HT2 receptors, was launched in 2009 by Schering-Plough for the acute treatment of schizophrenia [16]. It is worth noting that the endogenous ligands of both PPARγ and FFAR1 are fatty acids. Therefore, simultaneous activation of both PPARγ and FFAR1 should be well tolerated by the body, simulating the metabolic response after a fatty meal. Moreover, the concept of increasing insulin sensitivity and insulin secretion simultaneously has been successfully implemented using various marketed drug combinations as mentioned above.