Design, Synthesis And Evaluation Of Fused Heteropyrimidine Derivatives As GPR119 Agonist For Treatment Of Type 2 Diabetes

Diabetes mellitus has been considered to be a major health problem in the world in recent years and it is mainly divided into type 1 and type 2.The number of type 2diabetes accounts for the majority and the main feature is abnormal blood glucose(hyperglycemia)caused by insufficient insulin secretion in the pancreas.The type 2diabetes can easily cause serious cardiovascular diseases.There is no medicine to completely cure diabetes,so lowering blood sugar is still an effective means of controlling diabetes.Traditional hypoglycemic drugs on the market have different levels of side effects after long-term use.In this paper,the G protein-coupled receptor119 involved has a dual role of promoting GLP-1 release and directly improving insulin secretion.It has been one of the new targets for hypoglycemic drugs of type 2diabetes and has great merit prospect in reducing blood sugar.According to previous studies,5-nitro pyrimidine compounds have strong GPR119 agonistic activity,but nitro-compounds were prone to hepatotoxicity during metabolism in vivo.Therefore,this topic is mainly to modify the nuclear structure of nitropyrimidine to obtain a series of novel fused pyrimidine derivatives of GPR119 agonists.Based on the structure-activity relationship study(SAR)and the fragment drug design theory,we designed pyrimidopyrimidine,dihydrocyclopen-tadepyrimidine and tetrahydroquinazoline pyrimidine as the core structures and retained the conformationally restricted endo-bicycle of the active fragment.The endo-bicyclic ring is the head pharmacophore and the substituted fluorine-containing aniline is the tail pharmacophore.The 28 novel compounds were obtained by corresponding design route and chemical reaction conditions.The structures were detected by 1H-NMR and LC/MS.The strongest active compoundwas verified by cell and animal experiments.In the pyrimidine pyrimidine compounds vitro pharmacological activity study,two compounds 25a(2.2n M)and 31e(8.1n M)with better activity were obtained.At the same time,the activity study of dihydrocyclopentenopyrimidine and tetrahydroquinazolinopyrimidine compounds were obtained the most active compound 53(0.27 μM).In vitro activity data,the endo-bicyclic fragment and a fluoro-subtituted phenylamino group showed better agonistic activity.This may be introduced the fluorine atoms and improved the hydrophilicity of the compound.The tetrahydroquinazoline derivatives exhibited better GPR119 agonism than dihydrocyclopentenepyrimidine.Subsequently,the compounds 25 a and 31 e were subjected to a mouse glucose tolerance test,and the results showed that the compound25 a showed a significant decrease in glucose at a dose of 15 mg/kg.Although the pharmacological activity of this kind of compound is not as good as that of5-nitropyrimidine compound,it is more clearly demonstrated in the study of pharmacophores that the head-tail side chain has good agonistic activity and pyrimidine pyrimidine exhibits a strong pharmacodynamic advantage in fully stimulating the GPR119 receptor.This provided a basis for studying GPR119 full agonists.The modification will continue on the pyrimidopyrimidine ring in the later stage and expect to obtain the most valuable hypoglycemic drug candidates.