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  • br Results and discussion br Conclusion In summary starting


    Results and discussion
    Conclusion In summary, starting from our previous lead Milnacipran HCl 1, we replaced the 5-nitropyrimidine core with pyrimidopyrimidine to obtain a series of novel compounds as drug candidates of GPR119 agonist for treatment of type 2 diabetes. Some derivatives showed good agonistic activities (EC50 < 100 nM) and potency. SAR studies illustrated that pyrimidopyrimidine compounds bearing endo-bicyclic moiety were good for agonistic potency, which is consistent with our former results. And introduction of fluorine on aniline group could increase the GPR119 agonistic activity. Derivatives containing bicyclic amine was revealed better activities than bicyclic ether. As a result, optimized compounds 15a and 21e displayed more potent agonistic activities with single digit EC50 values (2.2 nM and 8.1 nM respectively), which were evaluated for their oGTT with the dose of 5 mg/kg or 15 mg/kg in C57BL/6N mice. Compound 15a exerted 13.5% reduction in blood glucose AUC0–2h at the dose of 15 mg/kg comparing with metformin reduced 18% of AUC0–2h at the dose of 300 mg/kg. Follow up studies and results will be reported in due course.
    Diabetes is a serious metabolic disorder that occurs when the pancreas does not produce enough insulin, or the body cannot effectively use existing insulin. Hyperglycemia (high blood glucose) can lead to various health consequences such as kidney damage, heart disease, stroke, nerve damage and blindness. Type 2 diabetes mellitus (T2DM, or noninsulin dependent), is the most common form of diabetes caused by insulin resistance, and loss of pancreatic β-cell function and approximately 95% diabetic patients are suffering from type 2 diabetes. This health burden is growing at an alarming rate, and it is estimated that there are approximately 350 million diabetic people globally. The prevalence of the disease is expected to escalate to 439 million by 2030., , Although, a variety of treatments are available for T2DM, many patients are unable to achieve their target HbA1c level. Considerable attention has been focused on overcoming this public health challenge worldwide. Hence, there is a strong need for novel approaches to achieve better glycemic control and normoglycemia. Strategies that promote significant glycemic control by limiting hypoglycemia and cardiovascular side effects by enhancing insulin secretion in a glucose dependent manner could offer robust treatment for T2DM. GPR119 is a member of the class A G protein-coupled receptor (GPCR) family, and it is highly expressed in pancreatic β-cells and intestinal endocrine cells., , Upon activation by its endogenous ligand, intracellular cAMP accumulates and adenylate cyclase activation enhances the effect of glucose-stimulated insulin secretion (GSIS) and GLP-1 release. Thus GPR119 represents a promising target for the treatment of type 2 diabetes and obesity owing to its ability to improve glucose homoeostasis while concurrently slowing gastric emptying, reducing food intake and promoting weight loss., Endogenous ligands for GPR-119 have been identified including lysophosphatidylcholine (LPC) and oleoylethanolamide (OEA)., , Moreover, numerous small molecule GPR119 agonists have been identified in recent years. Among them, structurally rigid bicyclic compounds were identified as promising scaffolds. These bicyclic analogues exhibited potent GPR119 agonistic activity, efficacy and PK profiles ()., , , , This prompted us to look for an alternate bicyclic scaffold, as a result, we identified the thienopyrimidine scaffold. In this present work we wish to report the synthesis and biological evaluation of thienopyrimidine derivatives as GPR119 agonists (). The general method for compound synthesis is outlined in . As shown in , commercially available Boc protected piperidine derivative was coupled with 6-bromo-4-chlorothieno[3,2-]pyrimidine to yield coupled product , which was treated with diverse aryl boronic acids by Suzuki coupling in the presence of palladium catalyst afforded compound with good yield. Meanwhile, Boc-protected piperidinone was converted to 4-methylaminopiperidine derivative via reductive amination, and it was then coupled with 6-bromo-4-chlorothieno[3,2-]pyrimidine, followed by Suzuki reaction to yield compound . Deprotection of compound with 4M HCl afforded compound , which was derivatized by diverse electrophiles to give the final thienopyrimide derivative .