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

Yang, Zunhua; Fang, Yuanying; Park, Haeil

doi:10.1016/j.bmcl.2017.03.092

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

Yang, Zunhua;
Fang, Yuanying;
Park, Haeil

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15

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18

초록

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 hEC(50) 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 (1.2 nM) and quite good agonistic activity (112.2% max) as a full agonist. (C) 2017 Elsevier Ltd. All rights reserved.

키워드

Pyrimidine derivatives; GPR119 agonist; Type 2 diabetes; endo-Azabicyclic ether/amine; Full agonist; PROTEIN-COUPLED RECEPTOR; GLYCEMIC CONTROL; DISCOVERY; POTENT; OPTIMIZATION; DESIGN; SERIES; G-PROTEIN-COUPLED-RECEPTOR-119; RELEASE; AGENTS

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

저자: Yang, Zunhua; Fang, Yuanying; Park, Haeil

DOI: 10.1016/j.bmcl.2017.03.092

발행일: 2017-06-01

유형: Article

저널명: Bioorganic & Medicinal Chemistry Letters

권: 27

호: 11

페이지: 2515 ~ 2519