Synthesis and biological evaluation of 5-nitropyrimidine analogs with azabicyclic substituents as GPR119 agonists

Zunhua Yang; Yuanying Fang; Tuan-Anh N Pham; Jongkook Lee; Haeil Park

doi:10.1016/j.bmcl.2012.12.011

Synthesis and biological evaluation of 5-nitropyrimidine analogs with azabicyclic substituents as GPR119 agonists

Bioorg Med Chem Lett. 2013 Mar 1;23(5):1519-21. doi: 10.1016/j.bmcl.2012.12.011. Epub 2012 Dec 20.

Authors

Zunhua Yang¹, Yuanying Fang, Tuan-Anh N Pham, Jongkook Lee, Haeil Park

Affiliation

¹ College of Pharmacy of Kangwon National University, Chuncheon 200-701, Republic of Korea.

PMID: 23374864
DOI: 10.1016/j.bmcl.2012.12.011

Abstract

5-Nitropyrimidine analogs substituted with conformationally restricted azabicyclic amines and alcohols were prepared and evaluated their agonistic activity against human GPR119. The analogs bearing endo-azabicyclic amines and alcohols (7, 8, 11, and 12) exhibited full agonistic activities while the analogs with exo-azabicyclic amines and alcohols were proved as partial agonists (9, 10, 13, and 14) regardless of their EC(50) values. 5-Nitropyrimidine analogs with (2-fluoro-4-methylsulfonyl)phenylamino group (8, 10, 12, 14) showed more potent GPR119 activation activities than the analogs without fluorine in all cases (7, 9, 11, 13).

MeSH terms

Azabicyclo Compounds / chemical synthesis*
Azabicyclo Compounds / chemistry
Azabicyclo Compounds / pharmacology*
Diabetes Mellitus, Type 2 / drug therapy
Humans
Molecular Conformation
Pyrimidines / chemical synthesis*
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Receptors, G-Protein-Coupled / agonists*
Structure-Activity Relationship

Substances

Azabicyclo Compounds
GPR119 protein, human
Pyrimidines
Receptors, G-Protein-Coupled