Peri-substituted hexahydro-indolones as novel, potent and selective human EP3 receptor antagonists

Matthew O'Connell; Wayne Zeller; James Burgeson; Rama K Mishra; Jose Ramirez; Alex S Kiselyov; Thornorkell Andrésson; Mark E Gurney; Jasbir Singh

doi:10.1016/j.bmcl.2008.12.027

Peri-substituted hexahydro-indolones as novel, potent and selective human EP3 receptor antagonists

Bioorg Med Chem Lett. 2009 Feb 1;19(3):778-82. doi: 10.1016/j.bmcl.2008.12.027. Epub 2008 Dec 10.

Authors

Matthew O'Connell¹, Wayne Zeller, James Burgeson, Rama K Mishra, Jose Ramirez, Alex S Kiselyov, Thornorkell Andrésson, Mark E Gurney, Jasbir Singh

Affiliation

¹ deCODE Chemistry, Inc., Medicinal Chemistry, 2501 Davey Road, Woodridge, IL 60517, USA.

PMID: 19121942
DOI: 10.1016/j.bmcl.2008.12.027

Abstract

A series of peri-substituted [4.3.0] bicyclic non-aromatic heterocycles have been identified as potent and selective hEP(3) receptor antagonists. These molecules adopt a hair-pin conformation that overlaps with the endogenous ligand PGE(2) and fits into an internally generated EP(3) pharmacophore model. Optimized compounds show good metabolic stability and improved solubility over their corresponding bicyclic aromatic analogs.

MeSH terms

Alprostadil / analogs & derivatives
Alprostadil / metabolism
Animals
CHO Cells
Chemistry, Pharmaceutical / methods
Cricetinae
Cricetulus
Drug Design
Humans
Indoles / chemical synthesis*
Indoles / pharmacology*
Inhibitory Concentration 50
Ligands
Magnetic Resonance Spectroscopy
Prostaglandins / chemistry
Receptors, Prostaglandin E / antagonists & inhibitors*
Receptors, Prostaglandin E / chemistry
Receptors, Prostaglandin E, EP3 Subtype
Sulfonamides / chemistry

Substances

Indoles
Ligands
PTGER3 protein, human
Prostaglandins
Receptors, Prostaglandin E
Receptors, Prostaglandin E, EP3 Subtype
Sulfonamides
prostaglandin E3
Alprostadil