title: 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.
authors.affiliation: Department of Pharmacology, School of Medicine, Emory University, 1510 Clifton Rd, Atlanta, GA 30322, USA. Electronic address: tganesh@emory.edu.
authors.forename: Thota
authors.initials: T
authors.lastname: Ganesh
authors.affiliation: Department of Pharmacology, School of Medicine, Emory University, 1510 Clifton Rd, Atlanta, GA 30322, USA.
authors.forename: Jianxiong
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology, School of Medicine, Emory University, 1510 Clifton Rd, Atlanta, GA 30322, USA.
authors.forename: Ray
authors.initials: R
authors.lastname: Dingledine
mesh_terms: D020106:Acrylamide / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D058307:Receptors, Prostaglandin E, EP2 Subtype; D020106:Acrylamide
keywords: Anti-inflammatory; Cyclic AMP; G protein-coupled receptor; Indole-amides; TR-FRET assay