title: Discovery of highly selective EP4 receptor agonists that stimulate new bone formation and restore bone mass in ovariectomized rats.
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.
authors.affiliation: 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
authors.forename: Kimberly O
authors.initials: KO
authors.lastname: Cameron
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Lefker
authors.forename: Margaret Y
authors.initials: MY
authors.lastname: Chu-Moyer
authors.forename: David T
authors.initials: DT
authors.lastname: Crawford
authors.forename: Paul DaSilva
authors.initials: PD
authors.lastname: Jardine
authors.forename: Shari L
authors.initials: SL
authors.lastname: DeNinno
authors.forename: Sandra
authors.initials: S
authors.lastname: Gilbert
authors.forename: William A
authors.initials: WA
authors.lastname: Grasser
authors.forename: HuaZhu
authors.initials: H
authors.lastname: Ke
authors.forename: Bihong
authors.initials: B
authors.lastname: Lu
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Owen
authors.forename: Vishwas M
authors.initials: VM
authors.lastname: Paralkar
authors.forename: Hong
authors.initials: H
authors.lastname: Qi
authors.forename: Dennis O
authors.initials: DO
authors.lastname: Scott
authors.forename: David D
authors.initials: DD
authors.lastname: Thompson
authors.forename: Christina M
authors.initials: CM
authors.lastname: Tjoa
authors.forename: Michael P
authors.initials: MP
authors.lastname: Zawistoski
mesh_terms: 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
chemical_list: C545652:Ptger4 protein, rat; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype