Yang Zunhua, Fang Yuanying, Park Haeil
College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China.
College of Pharmacy of Kangwon National University, Chuncheon 200-701, Republic of Korea.
Bioorg Med Chem Lett. 2017 Jun 1;27(11):2515-2519. doi: 10.1016/j.bmcl.2017.03.092. Epub 2017 Apr 2.
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 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 EC value (1.2nM) and quite good agonistic activity (112.2% max) as a full agonist.
设计、合成了一类带有多种构象受限氮杂双环醚/胺的新型嘧啶衍生物，并评估了它们针对2型糖尿病的GPR119激动剂活性。大多数化合物的人内皮细胞（hEC）值优于内源性脂质油酰乙醇胺（OEA）。芳环上有2-氟取代的类似物比没有氟的类似物表现出更强的GPR119激活作用。特别是由内型氮杂双环醇合成的化合物27m被观察到具有最佳的EC值（1.2 nM），并作为完全激动剂具有相当好的激动活性（最大活性的112.2%）。
