Discovery of highly selective EP4 receptor agonists that stimulate new bone formation and restore bone mass in ovariectomized rats

Kimberly O Cameron; Bruce A Lefker; Margaret Y Chu-Moyer; David T Crawford; Paul DaSilva Jardine; Shari L DeNinno; Sandra Gilbert; William A Grasser; HuaZhu Ke; Bihong Lu; Thomas A Owen; Vishwas M Paralkar; Hong Qi; Dennis O Scott; David D Thompson; Christina M Tjoa; Michael P Zawistoski

doi:10.1016/j.bmcl.2006.01.018

Discovery of highly selective EP4 receptor agonists that stimulate new bone formation and restore bone mass in ovariectomized rats

Bioorg Med Chem Lett. 2006 Apr 1;16(7):1799-802. doi: 10.1016/j.bmcl.2006.01.018. Epub 2006 Jan 26.

Authors

Kimberly O Cameron¹, Bruce A Lefker, Margaret Y Chu-Moyer, David T Crawford, Paul DaSilva Jardine, Shari L DeNinno, Sandra Gilbert, William A Grasser, HuaZhu Ke, Bihong Lu, Thomas A Owen, Vishwas M Paralkar, Hong Qi, Dennis O Scott, David D Thompson, Christina M Tjoa, Michael P Zawistoski

Affiliation

¹ Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA. kimberly.o.cameron@pfizer.com

PMID: 16442794
DOI: 10.1016/j.bmcl.2006.01.018

Abstract

Heptanoic acid lactams, exemplified by 2, were identified as highly selective EP4 agonists via high throughput screening. Lead optimization led to the identification of lactams with a 30-fold increase in EP4 potency in vitro. Compounds demonstrated robust bone anabolic effects when administered in vivo in rat models of osteoporosis.

MeSH terms

Animals
Bone Density / drug effects*
Bone Development*
Bone and Bones / drug effects*
Female
Organ Size / drug effects*
Osteoporosis
Ovariectomy*
Rats
Rats, Sprague-Dawley
Receptors, Prostaglandin E / agonists*
Receptors, Prostaglandin E, EP4 Subtype

Substances

Ptger4 protein, rat
Receptors, Prostaglandin E
Receptors, Prostaglandin E, EP4 Subtype