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  • In recent years several DPP IV inhibitors have already been


    In recent years, several DPP-IV inhibitors have already been approved, such as sitagliptin, vildagliptin, saxagliptin, tenegliptin, alogliptin and linagliptin, etc. Among them, linagliptin (1, Fig. 1) is a non-peptide mimetic 66 8 with a unique xanthine scaffold developed through high-throughput screening (HTS) [13]. Linagliptin displays the most potent and longest-lasting DPP-IV inhibition among marketed DPP-IV inhibitors [14]. In addition, G-protein-coupled receptor 119 (GPR119), predominantly expressed in pancreatic β-cells and enteroendocrine L-cells in the gut, has been a promising drug target for T2DM. The activation of GPR119 increases the intracellular accumulation of cyclic adenosine monophosphate (cAMP), leading to enhanced glucose-dependent insulin secretion and increased release of GLP-1 [15], [16], [17], [18], [19], [20], [21], [22]. To date, several pharmaceutical companies have progressed GPR119 agonists into the clinical study. Representative GPR119 agonists such as AR231453 (2), APD597 (3) and PSN632408 (4), are depicted in Fig. 1. Therefore, based on the biological effects of GLP-1, synergistic effects of DPP-IV inhibition and GPR119 agonism may be advantageous in blood glucose control. Indeed, in animal experiments, combining a GPR119 agonist with a DPP-IV inhibitor significantly increased plasma active GLP-1 levels and improved glucose clearance, exemplified by the combination of the GPR119 agonist AR231453 or PSN632408 with the DPP-IV inhibitor sitagliptin [23], [24]. These results inspired us to design a dual modulator targeting DPP-IV and GPR119 as an anti-diabetic agent. Compared to multi-component drugs, the multiple ligands approach may have a lower risk of drug-drug interactions, a simplified clinical development, and other potential therapy advantage [25], [26]. By merging main pharmacophore characteristics, a general structure 5 containing both a xanthine scaffold derived from linagliptin, and the GPR119 agoinsts common pharmacophore, i.e. 4-substituted piperidine fragment [16], are designed and synthesized (Fig. 2). We hypothesize that the linker between the xanthine and piperidine fragments, as well as R1 substituent on the right-hand xanthine and R2 substituent on the left-hand piperidine might modulate the potency of both DPP-IV and GPR119. Herein, we present the synthesis, SARs and the pharmacological effects of a series of xanthine derivatives. Systematic structural modification of general structure 5 afforded the identification of compound 20i, which displayed a selective DPP-IV inhibition, good GPR119 agonism activity, and favorable metabolic stability.
    Chemistry The synthesis of key intermediates 9a, 10a-g and 12a-b containing xanthine core is outlined in Scheme 1. The substituted piperidinyl intermediates 15a-d and 18a-p are synthesized following the procedures summarized in Scheme 2, Scheme 3. The general synthetic procedures of the target compounds 19a-m and 20a-o are illustrated in Scheme 4.
    Results and discussion The target compounds were evaluated in vitro for their inhibition of DPP-IV and DPP-8/9. The in vitro agonistic activities of the target compounds against GPR119 were also evaluated using GPR119 agonism assay. The inhibition against DPP-IV as IC50 values and the agonism to GPR119 as EC50 values of the selected compounds were summarized in Table 1, Table 2, Table 3 with sitagliptin and AR231453 as the corresponding reference compounds. The IC50 value represents the concentration of each compound resulting in 50% inhibition of DPP-IV. The relative activity percentages of the corresponding reference compounds are normalized to the activity of AR231453 at the same concentration and the EC50 value refers to the concentration of indicated compound reaching half potency of GPR119 agonism itself.
    Conclusion In summary, we have synthesized and characterized a series of xanthine derivatives as potent dual ligands targeting DPP-IV and GPR119 based on the pharmacophore merging approach. Systematic optimization led to the identification of compound 20i, which proved to be a dual modulator with potent and selective DPP-IV inhibition, good GPR119 agonism activity, and favorable metabolic stability. Docking study was performed to elucidate the potent DPP-IV inhibition of 20i. Further optimization based on the proof-of-concept compound 20i to discover more active compounds targeting both DPP-IV and GPR119 is in progress and will be reported in due course.