Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 82, Issue -, Pages 521-535Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2014.05.076
Keywords
G protein-coupled receptor; Indole-amides; Cyclic AMP; TR-FRET assay; Anti-inflammatory
Categories
Funding
- Alzheimer's Drug Discovery Foundation grant [20131001]
- NIH/NINDS grants [K99/R00NS082379, U01NS058158]
- NARSAD Young Investigator Grant [20940]
- Epilepsy Foundation grant [219142]
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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. (C) 2014 Elsevier Masson SAS. All rights reserved.
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