Development of second generation EP2 antagonists with high selectivity

• Type of Material: Article
• Authors: Thota Ganesh, Emory University; Jianxiong Jiang, Emory University; Raymond Dingledine, Emory University
• Language: English
• Date: 2014-07-23
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 Elsevier Masson SAS. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.ejmech.2014.05.076
• Title of Journal or Parent Work: European Journal of Medicinal Chemistry
• ISSN: 0223-5234
• Volume: 82
• Start Page: 521
• End Page: 535
• Grant/Funding Information: 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: Life Sciences & Biomedicine; MICE LACKING; TR-FRET assay; FERTILITY; Science & Technology; Indole-amides; ACTIVATION; Chemistry, Medicinal; Cyclic AMP; INHIBITION; PROSTANOID RECEPTORS; PGE(2); DISEASE; INFLAMMATION; Pharmacology & Pharmacy; Anti-inflammatory; PROSTAGLANDIN RECEPTOR EP2; G protein-coupled receptor; MODEL
• Research Categories: Health Sciences, Pharmacology

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.