Structure-activity relationship studies on ortho-substituted cinnamic acids, a new class of selective EP(3) antagonists

Michel Belley; Michel Gallant; Bruno Roy; Karine Houde; Nicolas Lachance; Marc Labelle; Laird A Trimble; Nathalie Chauret; Chun Li; Nicole Sawyer; Nathalie Tremblay; Sonia Lamontagne; Marie-Claude Carrière; Danielle Denis; Gillian M Greig; Deborah Slipetz; Kathleen M Metters; Robert Gordon; Chi Chung Chan; Robert J Zamboni

doi:10.1016/j.bmcl.2004.11.051

Structure-activity relationship studies on ortho-substituted cinnamic acids, a new class of selective EP(3) antagonists

Bioorg Med Chem Lett. 2005 Feb 1;15(3):527-30. doi: 10.1016/j.bmcl.2004.11.051.

Affiliation

¹ Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe Claire-Dorval, Québec, Canada H9R 4P8. belley@merck.com

PMID: 15664806
DOI: 10.1016/j.bmcl.2004.11.051

Abstract

A series of novel ortho-substituted cinnamic acids have been synthesized, and their binding activity and selectivity on the four prostaglandin E(2) receptors evaluated. Many of them are very potent and selective EP(3) antagonists (K(i) 3-10 nM), while compound 9 is a very good and selective EP(2) agonist (K(i) 8 nM). The biological profile of the EP(2) agonist 9 in vivo and the metabolic profile of selected EP(3) antagonists are also reported.

MeSH terms

Cell Line
Cinnamates / chemical synthesis*
Cinnamates / metabolism
Cinnamates / pharmacology*
Cyclic AMP / biosynthesis
Humans
Pharmacokinetics
Protein Binding
Receptors, Prostaglandin E / antagonists & inhibitors*
Receptors, Prostaglandin E, EP2 Subtype
Receptors, Prostaglandin E, EP3 Subtype
Structure-Activity Relationship

Substances

Cinnamates
PTGER2 protein, human
PTGER3 protein, human
Receptors, Prostaglandin E
Receptors, Prostaglandin E, EP2 Subtype
Receptors, Prostaglandin E, EP3 Subtype
Cyclic AMP