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GPR119 is a promising target for discovery of anti-type 2 diabetes mellitus agents. We described the optimisation of a novel series of pyrimido[5,4- b ][1,4]oxazine derivatives as GPR119 agonists. Most designed compounds exhibited good agonistic activities. Among them, compound 10 and 15 demonstrated the potent EC 50 values (13 and 12 nM, respectively) and strong inherent activities. Moreover, significant hypoglycaemic effect of compound 15 was observed by reducing the blood glucose AUC 0-2h at the dose of 30 mg/kg, which is stronger than Vildagliptin (23.4% reduction vs. 17.9% reduction).

A novel series of fused pyrimidine derivatives were designed, synthesized and evaluated as GPR119 agonists. Among them, cyclohexene fused compounds (tetrahydroquinazolines) showed greater GPR119 agonistic activities than did dihydrocyclopentapyrimidine and tetrahydropyridopyrimidine scaffolds. Analogues (16, 19, 26, 28, 42) bearing endo-N-Boc-nortropane amine and fluoro-substituted aniline exhibited better EC 50 values (0.27-1.2 μM) though they appeared to be partial agonists., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We described the discovery and optimization of a novel series of pyrimidopyrimidine derivatives as G-protein coupled receptor 119 (GPR119) agonists against type 2 diabetes. Most designed compounds displayed significant GPR119 agonistic activities. Optimized analogues 15a and 21e exhibited highly potent agonistic activities with single digit EC 50 values (2.2 nM and 8.1 nM, respectively). Therefore, 15a and 21e were evaluated for their oral glucose tolerance test (oGTT) in C57BL/6N mice. Compound 15a reduced the blood glucose area of under curve from 0 to 2 h (AUC 0-2h ) to 13.5% at the dose of 15 mg/kg comparing with Metformin reduced 18% of AUC 0-2h at the dose of 300 mg/kg., (Copyright © 2018 Elsevier Ltd. All rights reserved.)