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  • Vinpocetine The synthesis of nitropyrimidine analogs was out

    2022-05-10

    The synthesis of 5-nitropyrimidine analogs – was outlined in . 4,6-Dichloro-5-nitropyrimidine, 4-methylsulfonylaniline and 2-fluoro-4-methylsulfonylaniline were prepared according to previously reported procedures., , Reaction of 4,6-dichloro-5-nitropyrimidine and substituted aniline in DMF yielded compounds and , following by treatment with diverse azabicyclic alcohol or amine to afford target compounds –. Analogs – were evaluated for their abilities to activate the human GPR119 in a cell-based cAMP assay, which were expressed in EC and %max values. The EC values represent the concentration of the tested compounds for 50% cAMP stimulation of oleoylethanolamide (OEA), while the %max values present the relative response (%) of the tested compounds compared to the maximal effect of OEA. illustrated the biological results of compounds –. Among these analogs, compounds bearing 2-fluoro-4-methylsulfonyl aniline group showed more potent GPR119 activation activities than 4-methylsulfonylaniline group. And most compounds synthesized from -azabicyclic moiety exhibited superior EC values and stronger agonistic activities comparing with those containing -azabicyclic moiety. Especially, compounds , , , , , , , displayed strong ECs (single digit nM). However, derivatives , , , , were observed middle level %max values and proved as partial agonists. Moreover, several derivatives only with -azabicyclic scaffold were proved as full agonists basted on %max values. Furthermore, Vinpocetine bearing -azabicyclic amine revealed the potent EC value (1.8nM) with good efficacy (104.3% max). And compound containing -azabicyclic alcohol showed the quite good efficacy (112.2% max) with best EC value (1.2nM). In summary, we discovered a new series of 5-nitropyrimidine analogs with diverse aza-bicyclic ether or amine as GPR119 gonists for treatment of type 2 diabetes. As a result, most derivatives exhibited the significant GPR119 activation activities. All compounds containing 2-fluoro-4-methylsulfonyl aniline fragment showed more potent GPR119 agonistic activities than those with 4-methylsulfonylaniline group, which indicated fluorine atom as a hydrogen bond receptor was benefit for the activation activity. And analogs bearing -azabicyclic scaffold exhibited better %max values and were proved as full agonists comparing with -azabicyclic moiety, which implied that -azabicyclic moiety might be “agonist conformation”. It is exciting that compounds , , , , , , , displayed single digit nM of EC Values. Notably, the analog showed potent agonistic activity (104.3% max) with strong EC value (1.8 nM) while the analog revealed maximum agonistic activity (112.2% max) with quite good EC value (1.2nM). These results encourage us to search other heterocyclic structures as parents ring with -azabicyclic moiety to investigate the structure activity relationship of ligands with GPR119. The follow-up studies and results will be reported in due course. Acknowledgements This research was supported by the Korea Research Foundation (2013R1A1A2007509). The authors thank to Dr. Moon Ho Son (Dong-A Pharm. Co. Ltd) for hGPR119 agonist activity assay. We also thank to Pharmaceutical Research Institute and Central Laboratory of Kangwon National University for the use of analytical instruments and bioassay facilities.
    Increasing glucose-dependent insulin secretion from the pancreas is a hallmark for the treatment of type 2 diabetes patients. Upon ingestion of long-chain monosaturated fatty acids (MSFAs) present in diets containing carbohydrates and fat, insulin secretion is triggered via several distinct mechanisms: For example, insulin release may be triggered upon binding of MSFAs directly to receptors on pancreatic β cells, such as GPR40, or indirectly upon secretion of incretins (GLP1, GIP, etc.) from enteroendocrine L-cells which in turn act on the appropriate receptors in β cells. The Gα-protein-coupled receptor GPR119 is predominantly expressed in both pancreatic β cells and in enteroendocrine L-cells, stimulating both insulin and incretin secretion in a complementary fashion. GPR119 agonists may therefore provide an exciting and novel approach to the treatment of type-2 diabetes and obesity., , ,