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: [email protected].
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.