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  • Introduction GPR is a class A type of

    2021-11-29

    Introduction GPR119 is a class A type of G Protein coupled receptor, which is expressed primarily in pancreatic β-cells and the K and L Lithocholic Acid of the gastrointestinal tract [1], [2], [3]. Activation of GPR119 promotes secretion of incretins such as glucagon-like peptide-1 (GLP-1) in the intestinal tract and glucose dependent release of insulin in pancreatic β-cells [4], [5], [6], [7], [8]. The dual mechanism makes GPR119 a promising target for discovery of anti-diabetic agents with low risk of hypoglycemia. Arena researchers disclosed the first potent and oral small molecule AR231453 as GPR119 agonist [9]. Following this discovery, numerous synthetic GPR119 agonists have been subsequently reported, some of which have advanced into clinical trials (Fig. 1) [10], [11]. We have previously investigated AR231453 from among the reported agonists, choosing it as the lead compound. A series of 5-nitropyrimidine derivatives bearing azabicyclic alcohols/amines were synthesized and evaluated for their GPR119 agonistic activities [12], [13], [14]. Although these 5-nitropyrimidine compounds displayed potent biological activities, nitro-compound always caused hepatotoxicity [15], [16]. In our attempts to optimize the core skeleton, we have designed various fused pyridine moiety to replace 5-nitropyrimidine ring, using the strategy of scaffold hopping. In addition to heterocycle fused pyrimidine, we also studied the effect of lipophilic, cycloolefin-fused pyrimidine on the agonistic activity. We herein reported our efforts to expand the SAR study of GPR119 agonists with a series of novel fused pyrimidine derivatives, evaluating them for their human GPR119 activities. We will focus on the various core to see whether or not the pharmacophores are beneficial for bioactivity. The azabicyclic fragments and substituted anilines were retained (Fig. 2). Two conformations (endo and exo) of azabicyclic amines were explored to study the bioactivity relationship of the new core with endo/exo azabicyclic ring.
    Results and discussion
    Conclusion In summary, we designed, synthesized and evaluated a novel series of GPR119 agonists bearing dihydrocyclopentapyrimidine, tetrahydroquinazoline or tetrahydropyridopyrimidine as the core to replace the 5-nitropyrimidine scaffold. As a result, most compounds exhibited stronger EC50 values than that of OEA. Compounds containing endo-azabicyclic fragment and (2-fluoro-4-methylsulfonyl)phenylamino group or (2-fluoro-4-cyano)phenylamino group exhibited better EC50 values even though they appeared to be partial agonists. And tetrahydroquinazoline derivatives showed better GPR119 agonistic activities than did dihydrocyclopentapyrimidine and tetrahydropyridopyrimidine derivatives. But all these compounds displayed weaker potency than 5-nitropyrimidine derivatives. Furthermore, tetrahydroquinazoline 28 with endo-N-Boc-nortropane amine and (2-fluoro-4-methylsulfonyl)aniline displayed a good EC50 value (0.27 μM) and moderate GPR119 agonistic activity (71.5%). Subsequently, compound 28 displayed the dose-dependent effect in oGTT of C57BL/6N mice but a weak glucose-lowering effect. Further SAR study about various fused pyrimidine compounds is ongoing, and will be reported in due course.
    Experimental
    Acknowledgments This work was supported by National Natural Science Foundation of China (81460526), Jiangxi Provincial Department of Science and Technology (20171BAB205103, 20181BAB215043), Hongcheng Haiou Plan of Nanchang City (Zunhua Yang, 2017) and Health and Family Planning Commission of Jiangxi Province (2017A297, 20185521 and 20185523). The authors appreciate Drs. Robert Smith and Amy Dykstra for the manuscript revision.
    GPR119 is a G protein-coupled receptor (GPCR) expressed predominantly in pancreatic beta cells and enteroendocrine cells. Activation of GPR119 promotes glucose-dependent insulin release in the pancreas and secretion of incretins such as glucagon-like peptide-1 (GLP-1) in the gut. GPR119 has the potential to be a suitable target for the development of orally active, small molecule agonists and has received attention from many pharmaceutical companies in recent years.