Synthesis and biological evaluation of pyrimidine derivatives with diverse azabicyclic ether/amine as novel GPR119 agonist

Bioorg Med Chem Lett. 2017 Jun 1;27(11):2515-2519. doi: 10.1016/j.bmcl.2017.03.092.

Zunhua Yang ¹, Yuanying Fang ¹, Haeil Park ²

Affiliations

1 College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China.
2 College of Pharmacy of Kangwon National University, Chuncheon 200-701, Republic of Korea. Electronic address: haeilp@kangwon.ac.kr.

PMID: 28408218 DOI: 10.1016/j.bmcl.2017.03.092

Abstract

A class of novel pyrimidine derivatives bearing diverse conformationally restricted azabicyclic ether/amine were designed, synthesized and evaluated for their GPR119 Agonist activities against type 2 diabetes. Most compounds exhibited superior hEC₅₀ values to endogenous lipid oleoylethanolamide (OEA). Analogs with 2-fluoro substitution in the aryl ring showed more potent GPR119 activation than those without fluorine. Especially compound 27m synthesized from endo-azabicyclic alcohol was observed to have the best EC₅₀ value (1.2nM) and quite good agonistic activity (112.2% max) as a full agonist.

Keywords

Full agonist; GPR119 agonist; Pyrimidine derivatives; Type 2 diabetes; endo-Azabicyclic ether/amine.

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