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Author Notes:
Thota Ganesh: Tel.: +1-404-727-7393; Fax: +1-404-727-0365; tganesh@emory.edu
T.G. and R.D. designed the research; T.G. and J.J. performed the research; T.G. wrote the manuscript and R.D. helped with the writing.
Subject:
Research Funding:
This work was supported by Alzheimer’s Drug Discovery Foundation (T.G.); NIH/NINDS grants K99/R00NS082379 (to J.J.) and U01NS058158 (to R.D.); NARSAD Young Investigator Grant (to J.J.); and the Epilepsy Foundation (to J.J.).
Keywords:
- Science & Technology
- Life Sciences & Biomedicine
- Chemistry, Medicinal
- Pharmacology & Pharmacy
- G protein-coupled receptor
- Indole-amides
- Cyclic AMP
- TR-FRET assay
- Anti-inflammatory
- PROSTAGLANDIN RECEPTOR EP2
- PROSTANOID RECEPTORS
- MICE LACKING
- INFLAMMATION
- INHIBITION
- ACTIVATION
- FERTILITY
- DISEASE
- PGE(2)
- MODEL
Development of second generation EP2 antagonists with high selectivity
Abstract:
EP2 receptor has emerged as an important biological target for therapeutic intervention. In particular, it has been shown to exacerbate disease progression of a variety of CNS and peripheral diseases. Deletion of the EP2 receptor in mouse models recapitulates several features of the COX-2 inhibition, thus presenting a new avenue for anti-inflammatory therapy which could bypass some of the adverse side effects observed by the COX-2 inhibition therapy. We have recently reported a cinnamic amide class of EP2 antagonists with high potency, but these compounds exhibited a moderate selectivity against prostanoid receptor DP1. Moreover they possess acrylamide moiety in the structure, which may result in liver toxicity over longer period of use in a chronic disease model. Thus, we now developed a second generation compounds that devoid of the acrylamide functionality and possess high potency and improved (>1000-fold) selectivity to EP2 over other prostanoid receptors.
Copyright information:
© 2014 Elsevier Masson SAS. All rights reserved.
This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).
