title: Discovery and characterization of carbamothioylacrylamides as EP2selective antagonists.
abstract: Prostanoid receptor EP2 is emerging as a novel target for development of anti-inflammatory drugs for the treatment of chronic neurodegenerative and peripheral diseases; however, the availability of EP2 antagonist probes for exploration of peripheral disease models is very limited. We now report identification and characterization of a novel chemical class of compounds that show nanomolar potency and competitive antagonism of the EP2 receptor. A compound in this class, TG6-129, showed prolonged plasma half-life and did not cross the blood brain barrier. This compound also suppressed the induction of inflammatory mRNA markers in a macrophage cell line upon activation of EP2. Thus, this compound could be useful as a probe for a variety of peripheral chronic inflammatory diseases such as rheumatoid arthritis and chronic obstructive pulmonary disease, in which EP2 appears to play a pathogenic role.
authors.affiliation: Department of Pharmacology, School of Medicine, Emory University, Atlanta, Georgia 30322, United States.
authors.forename: Thota
authors.initials: T
authors.lastname: Ganesh
authors.forename: Jianxiong
authors.initials: J
authors.lastname: Jiang
authors.forename: Rangaiah
authors.initials: R
authors.lastname: Shashidharamurthy
authors.forename: Ray
authors.initials: R
authors.lastname: Dingledine
keywords: EP2 antagonist; EP2 receptor; Inflammation; acrylamides; cytokines; macrophage
references.citation: Neurobiol Aging. 2000 May-Jun;21(3):383-421
references.pmid: 10858586
references.citation: Biosci Biotechnol Biochem. 2008 Oct;72(10):2739-49
references.pmid: 18838795
references.citation: N Engl J Med. 2011 Dec 8;365(23):2205-19
references.pmid: 22150039
references.citation: Circ Res. 2008 Apr 25;102(8):986-93
references.pmid: 18323528
references.citation: Free Radic Biol Med. 2010 Jan 15;48(2):240-54
references.pmid: 19892012
references.citation: Expert Opin Ther Pat. 2011 Sep;21(9):1339-432
references.pmid: 21714592
references.citation: Respirology. 2008 Nov;13(7):1014-21
references.pmid: 18699805
references.citation: Prostaglandins Other Lipid Mediat. 2010 Apr;91(3-4):104-12
references.pmid: 19808012
references.citation: J Pharmacol Exp Ther. 2013 Feb;344(2):360-7
references.pmid: 23192657
references.citation: J Immunol. 2007 Jun 15;178(12):8138-47
references.pmid: 17548652
references.citation: Nature. 1998 Dec 3;396(6710):474-7
references.pmid: 9853756
references.citation: Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2307-12
references.pmid: 20080612
references.citation: Science. 2012 Jun 15;336(6087):1386-7
references.pmid: 22700906
references.citation: Mol Pharmacol. 1999 Apr;55(4):625-31
references.pmid: 10101019
references.citation: Nat Rev Mol Cell Biol. 2003 Sep;4(9):733-8
references.pmid: 14506476
references.citation: Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):3149-54
references.pmid: 22323596
references.citation: Br J Pharmacol. 2006 Jan;147 Suppl 1:S232-40
references.pmid: 16402109
references.citation: Lancet. 2007 May 12;369(9573):1627-40
references.pmid: 17499605
references.citation: J Biol Chem. 2013 Mar 29;288(13):9293-302
references.pmid: 23404506
references.citation: Science. 2004 Dec 10;306(5703):1954-7
references.pmid: 15550624
references.citation: Anal Chem. 2000 Apr 15;72(8):1781-7
references.pmid: 10784141
references.citation: JAMA. 2003 Jun 4;289(21):2819-26
references.pmid: 12783912
references.citation: Curr Drug Metab. 2005 Jun;6(3):161-225
references.pmid: 15975040
references.citation: J Exp Med. 2006 Feb 20;203(2):325-35
references.pmid: 16446378
references.citation: Chem Rev. 2011 Oct 12;111(10):6209-30
references.pmid: 21819041
references.citation: Arthritis Rheum. 2007 Aug;56(8):2608-19
references.pmid: 17665454
references.citation: Physiol Rev. 1999 Oct;79(4):1193-226
references.pmid: 10508233
references.citation: Br J Pharmacol. 2011 Dec;164(7):1847-56
references.pmid: 21595651
references.citation: Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3591-6
references.pmid: 23401547
references.citation: Annu Rev Med. 2010;61:17-33
references.pmid: 20059330
references.citation: Curr Opin Neurol. 2005 Jun;18(3):315-21
references.pmid: 15891419