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  • The GLU Epac transgenic mouse enabled us to monitor cAMP


    The GLU-Epac transgenic mouse enabled us to monitor cAMP responses to GPR119 ligands in individual primary cultured L-cells. Not all L-cells were found to be responsive to AR231453, suggesting there may be a subpopulation of L-cells that do not express functional GPR119. There was a tendency for smaller and less frequent cAMP responses to AR231453 in the small intestine compared with the colon, although this did not reach statistical significance. These results do, however, mirror the gradient of GLP-1 secretory responses in cultures from the different regions. In line with these findings, we also reported previously that Gpr119 expression appeared higher in colonic than small intestinal L-cells by qRT-PCR [23]. Mice with targeted Reserpine hydrochloride of Gpr119 in L-cells exhibited a marked reduction of plasma GLP-1 levels after gastric oil gavage. This suggests that GPR119-dependent detection of luminally-generated 2-monoacylglycerols or locally-released OEA plays a major role in the post-prandial GLP-1 secretory response to orally ingested triglycerides. While long chain free fatty acids are also released during the luminal digestion of corn and olive oils, and are sensed by GPR119-independent pathways, likely involving GPR40 and GPR120 [4], our findings suggest that these pathways play a relatively minor role compared with GPR119 in mediating the GLP-1 secretory response to oral lipids. While our data support the development of GPR119 agonists to enhance GLP-1 secretion, the role of different intestinal regions in post-prandial physiology and as drug targets deserves further attention.
    Introduction Type 2 diabetes mellitus (T2DM), a progressive chronic disease, is characterized by the inability of the human body to keep the blood glucose level in the required and balanced range in the fed and/or fasting state.1, 2, 3 The number of people with T2DM worldwide is more than 300 million, and the prevalence is predicted to rise to 642 million by 2040.4, 5, 6 In clinical therapy for T2DM, multiple antidiabetic agents such as insulin, metformin, thiazolidiones (TZDs), sulfonylurea derivatives (SUs), glucagon-like peptide 1 (GLP-1) analogues and dipeptidyl peptidase 4 (DPP4) inhibitors have been used. However, many patients are still unable to achieve their target glycemic control and all current diabetes drugs have known adverse effects. Therefore, new drugs with greater safety and efficacy are strongly needed for treatment of diabetes. GPR119 is a class A type of G Protein coupled receptor, which is expressed primarily in pancreatic β-cells and the K and L cells of the gastrointestinal tract.9, 10 Oleoylethanolamide (OEA) and N-oleoyldopamine (OLDA) have been identified and investigated for their biological effects as endogenous natural GPR119 agonists (Fig. 1).11, 12, 13 The stimulation of GPR119 could increase the cellular cAMP levels, leading to glucose-dependent insulin secretion from pancreatic β-cells and incretin release.14, 15, 16 The dual mechanism makes GPR119 a promising target for discovery of antidiabetic agents. After Arena researchers disclosed the first potent and oral small molecule GPR119 agonist, in the form of AR231453, a number of pharmaceutical companies and academic institutes devoted to develop GPR119 agonists against T2DM.17, 18, 19, 20, 21, 22 To date, a few compounds as GPR119 agonists such as MBX-2982, DS-8500a, BMS-903452, LEZ763, ZYG-19 have been pushed into clinical trials. However, none of them has been approved by FDA (Fig. 2).5, 23 So more and more scaffolds have been discovered and evaluated for their anti-diabetes potency. We previously reported a series of 5-nitropyrimidine and quinazoline derivatives as GPR119 agonist. Among them, compound 1 containing 5-nitropyrimidine with an endo-azabicyclic amino fragment exhibited potent and full GPR119 agonistic activity (EC50 = 1.5 nM).24, 25 But nitro-compound always shows the hepatotoxicity. We found the fused 4,8-disubstitute pyrimidopyrimidine could be the molecular variation of 5-nitropyrimidine with similar structures and easily obtainable from synthetic precursor of dipyridamole. Therefore, we designed to replace the 5-nitropyrimidine with pyrimidopyrimidine. Then three anilinos substituted by electron-withdrawing groups (EWG) were introduced as head moiety connected to the new scaffold (Fig. 3). We also retained endo- and exo-azabicyclic fragments as tail moiety to confirm the rationality of scaffold hopping in the interaction and to investigate the relationship between the conformations and agonistic activity. In this paper, we described the synthesis and biological evaluation of a series of pyrimidopyrimidine compounds as GPR119 agonist.