Novel 5-nitropyrimidine derivatives bearing endo-azabicyclic alcohols/amines as potent GPR119 agonists.
A series of GPR119 agonists based on a 5-nitropyrimidine scaffold bearing endo-azabicyclic substituents were synthesized and evaluated for their GPR119 agonistic activities. Most compounds exhibited much stronger EC50values than that of oleoylethanolamide (OEA). Among them, derivatives from endo-azabicyclic alcohols displayed more potent GPR119 agonistic activities than compounds with endo-azabicyclic amines. Especially the optimized compounds (6, 7, 8, 12, 17) were shown to have potent biological activities and were identified as full agonists. Isopropyl carbamate compound 8 synthesized from endo-azabicyclic alcohol was observed to have the best EC50value (0.6nM). Generally 2-fluoro substitution of the aryl group at the C4 position of 5-nitropyrimidine scaffold resulted in the increase of biological activity.
College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China.
Yuanying
Y
Fang
College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China.
Zunhua
Z
Yang
College of Pharmacy of Kangwon National University, Chuncheon 200-701, Republic of Korea.
Shankariah
S
Gundeti
College of Pharmacy of Kangwon National University, Chuncheon 200-701, Republic of Korea.
Jongkook
J
Lee
College of Pharmacy of Kangwon National University, Chuncheon 200-701, Republic of Korea. Electronic address: haeilp@kangwon.ac.kr.
Haeil
H
Park
D057809:HEK293 Cells; D006801:Humans; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013450:Sulfones / Q000138:chemical synthesis / Q000494:pharmacology*; D014326:Tropanes / Q000138:chemical synthesis / Q000494:pharmacology*
C519854:GPR119 protein, human; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; D013450:Sulfones; D014326:Tropanes; C000625531:isopropyl 3-(6-(2-fluoro-4-(methylsulfonyl)phenylamino)-5-nitropyrimidin-4-yloxy)-8-azabicyclo(3.2.1)octane-8-carboxylate
5-Nitropyrimidine; Full agonists; GPR119 agonists; endo-Azabicyclic alcohol