Discovery of highly selective EP4 receptor agonists that stimulate new bone formation and restore bone mass in ovariectomized rats.
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.
Cameron
Kimberly O
KO
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
Lefker
Bruce A
BA
Chu-Moyer
Margaret Y
MY
Crawford
David T
DT
Jardine
Paul DaSilva
PD
DeNinno
Shari L
SL
Gilbert
Sandra
S
Grasser
William A
WA
Ke
HuaZhu
H
Lu
Bihong
B
Owen
Thomas A
TA
Paralkar
Vishwas M
VM
Qi
Hong
H
Scott
Dennis O
DO
Thompson
David D
DD
Tjoa
Christina M
CM
Zawistoski
Michael P
MP
D000818:Animals; D015519:Bone Density / Q000187:drug effects*; D001846:Bone Development; D001842:Bone and Bones / Q000187:drug effects*; D005260:Female; D009929:Organ Size / Q000187:drug effects*; D010024:Osteoporosis; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000819:agonists*; D058309:Receptors, Prostaglandin E, EP4 Subtype
C545652:Ptger4 protein, rat; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype