Optimisation of novel 4, 8-disubstituted dihydropyrimido[5,4-b][1,4]oxazine derivatives as potent GPR 119 agonists

Abstract

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 EC₅₀ 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).

Keywords:

• Optimisation
• pyrimidodihydrooxazine
• GPR 119 agonists
• type 2 diabetes mellitus

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was financially supported by National Natural Science Foundation of China [81460526], Jiangxi Provincial Department of Science and Technology [20171BAB205103, 20181BAB215043, 20192ACB21012], Education Department of Jiangxi Province on Science and Technology Project Foundation [GJJ180667] and Traditional Chinese pharmacology discipline construction of Jiangxi University of Traditional Chinese Medicine [JXSYLXK-ZHYAO013].