title: 5-Cyano-6-oxo-1,6-dihydro-pyrimidines as potent antagonists targeting exchange proteins directly activated by cAMP.
abstract: Exchange proteins directly activated by cAMP (Epac) are a family of guanine nucleotide exchange factors that regulate a wide variety of intracellular processes in response to second messenger cAMP. To explore the structural determinants for Epac antagonist properties of high throughput screening (HTS) hit ESI-08, pyrimidine 1, a series of 5-cyano-6-oxo-1,6-dihydro-pyrimidine analogues have been synthesized and evaluated for their activities for Epac inhibition. Structure-activity relationship (SAR) analysis led to the identification of three more potent Epac antagonists (6b, 6g, and 6h). These inhibitors may serve as valuable pharmacological probes for further elucidation of the physiological functions and mechanisms of Epac regulation. Our SAR results and molecular docking studies have also revealed that further optimization of the moieties at the C-6 position of pyrimidine scaffold may allow us to discover more potent Epac-specific antagonists.
authors.affiliation: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Haijun
authors.initials: H
authors.lastname: Chen
authors.forename: Tamara
authors.initials: T
authors.lastname: Tsalkova
authors.forename: Fang C
authors.initials: FC
authors.lastname: Mei
authors.forename: Yaohua
authors.initials: Y
authors.lastname: Hu
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Cheng
authors.forename: Jia
authors.initials: J
authors.lastname: Zhou
mesh_terms: D003198:Computer Simulation; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology*; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D057809:HEK293 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D008958:Models, Molecular; D009570:Nitriles / Q000138:chemical synthesis* / Q000494:pharmacology; D010766:Phosphorylation; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D009570:Nitriles; D020033:Protein Isoforms; D011743:Pyrimidines; D054852:Small Molecule Libraries; D000242:Cyclic AMP; D051057:Proto-Oncogene Proteins c-akt