title: Nonpeptide alphavbeta3 antagonists. 8. In vitro and in vivo evaluation of a potent alphavbeta3 antagonist for the prevention and treatment of osteoporosis.
abstract: 3(S)-(6-methoxypyridin-3-yl)-3-[2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)propyl]imidazolidin-1-yl]propionic acid 6 was identified as a potent and selective antagonist of the alpha(v)beta(3) receptor. This compound has an excellent in vitro profile (IC(50) = 0.08 nM), a significant unbound fraction in human plasma (12%), and good pharmacokinetics in rat, dog, and rhesus monkey. On the basis of the efficacy shown in three in vivo models of bone turnover, the compound was selected for clinical development. To support the ongoing metabolism and safety studies, a novel strategy was employed in which a series of oxidized derivatives of 6 were prepared by exposure of 6 (or the methyl ester) to chemical oxidizing agents. These products proved useful in the identification of active metabolites generated by either in vitro or in vivo metabolism.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. john_hutchinson@merck.com
authors.forename: John H
authors.initials: JH
authors.lastname: Hutchinson
authors.forename: Wasyl
authors.initials: W
authors.lastname: Halczenko
authors.forename: Karen M
authors.initials: KM
authors.lastname: Brashear
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Breslin
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
authors.forename: Le T
authors.initials: LT
authors.lastname: Duong
authors.forename: Carmen
authors.initials: C
authors.lastname: Fernandez-Metzler
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gentile
authors.forename: John E
authors.initials: JE
authors.lastname: Fisher
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.forename: Joel R
authors.initials: JR
authors.lastname: Huff
authors.forename: Donald B
authors.initials: DB
authors.lastname: Kimmel
authors.forename: Chih-Tai
authors.initials: CT
authors.lastname: Leu
authors.forename: Robert S
authors.initials: RS
authors.lastname: Meissner
authors.forename: Kara
authors.initials: K
authors.lastname: Merkle
authors.forename: Rose
authors.initials: R
authors.lastname: Nagy
authors.forename: Brenda
authors.initials: B
authors.lastname: Pennypacker
authors.forename: James J
authors.initials: JJ
authors.lastname: Perkins
authors.forename: Thomayant
authors.initials: T
authors.lastname: Prueksaritanont
authors.forename: Gideon A
authors.initials: GA
authors.lastname: Rodan
authors.forename: Sandor L
authors.initials: SL
authors.lastname: Varga
authors.forename: Greg A
authors.initials: GA
authors.lastname: Wesolowski
authors.forename: Amy E
authors.initials: AE
authors.lastname: Zartman
authors.forename: Sevgi B
authors.initials: SB
authors.lastname: Rodan
authors.forename: Mark E
authors.initials: ME
authors.lastname: Duggan
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001862:Bone Resorption / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D004285:Dogs; D005260:Female; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D008253:Macaca mulatta; D008297:Male; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010024:Osteoporosis / Q000188:drug therapy / Q000517:prevention & control; D010052:Ovariectomy; D010084:Oxidation-Reduction; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C478626:3-(6-methoxypyridin-3-yl)-3-(2-oxo-3-(3-(5,6,7,8-tetrahydro(1,8)naphthyridin-2-yl)propyl)imidazolidin-1-yl)propionic acid; D039302:Integrin alphaVbeta3; D009287:Naphthyridines; D011422:Propionates