Document Detail


Identification and characterization of small molecules as potent and specific EPAC2 antagonists.
MedLine Citation:
PMID:  23286832     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
EPAC1 and EPAC2, two isoforms of exchange proteins directly activated by cAMP (EPAC), respond to the second messenger cAMP and regulate a wide variety of intracellular processes under physiological and pathophysiological circumstances. Herein, we report the chemical design, synthesis, and pharmacological characterization of three different scaffolds (diarylsulfones, N,N-diarylamines, and arylsulfonamides) as highly potent and selective antagonists of EPAC2. Several selective EPAC2 antagonists have been identified including 20i (HJC0350), which has an apparent IC(50) of 0.3 μM for competing with 8-NBD-cAMP binding of EPAC2 and is about 133-fold more potent than cAMP. Compounds 1 (ESI-05), 14c (HJC0338), and 20i, selected from each series, have exhibited no inhibition of EPAC1-mediated Rap1-GDP exchange activity at 25 μM, indicating that they are EPAC2-specific antagonists. Moreover, live-cell imaging studies using EPAC1, EPAC2, or PKA FRET sensor also demonstrate that 20i functions as an EPAC2 specific antagonist.
Authors:
Haijun Chen; Tamara Tsalkova; Oleg G Chepurny; Fang C Mei; George G Holz; Xiaodong Cheng; Jia Zhou
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-15
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  56     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-02-15     Completed Date:  2013-04-19     Revised Date:  2014-02-17    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  952-62     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Guanine Nucleotide Exchange Factors / antagonists & inhibitors*
Humans
Inhibitory Concentration 50
Magnetic Resonance Spectroscopy
Small Molecule Libraries*
Spectrometry, Mass, Electrospray Ionization
Structure-Activity Relationship
Grant Support
ID/Acronym/Agency:
P30 DA028821/DA/NIDA NIH HHS; P30DA028821/DA/NIDA NIH HHS; R01 DK069575/DK/NIDDK NIH HHS; R01 GM066170/GM/NIGMS NIH HHS; R01GM066170/GM/NIGMS NIH HHS; R21 MH093844/MH/NIMH NIH HHS; R21 NS066510/NS/NINDS NIH HHS; R21MH093844/MH/NIMH NIH HHS; R21NS066510/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Guanine Nucleotide Exchange Factors; 0/RAPGEF4 protein, human; 0/Small Molecule Libraries
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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