title: Nonpeptide alphavbeta3 antagonists. Part 11: discovery and preclinical evaluation of potent alphavbeta3 antagonists for the prevention and treatment of osteoporosis.
abstract: 3-(S)-Pyrimidin-5-yl-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid (5e) and 3-(S)-(methylpyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid (5f) were identified as potent and selective antagonists of the alpha(v)beta(3) receptor. These compounds have excellent in vitro profiles (IC(50) = 0.07 and 0.08 nM, respectively), significant unbound fractions in human plasma (6 and 4%), and good pharmacokinetics in rat, dog, and rhesus monkey. On the basis of the efficacy shown in an in vivo model of bone turnover following once-daily oral administration, these two compounds were selected for clinical development for the treatment of osteoporosis.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
authors.forename: Karen M
authors.initials: KM
authors.lastname: Brashear
authors.forename: Ben C
authors.initials: BC
authors.lastname: Askew
authors.forename: John H
authors.initials: JH
authors.lastname: Hutchinson
authors.forename: Carol A
authors.initials: CA
authors.lastname: McVean
authors.forename: Le T
authors.initials: LT
authors.lastname: Duong
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Feuston
authors.forename: Carmen
authors.initials: C
authors.lastname: Fernandez-Metzler
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gentile
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.forename: Donald B
authors.initials: DB
authors.lastname: Kimmel
authors.forename: Chih-Tai
authors.initials: CT
authors.lastname: Leu
authors.forename: Lorraine
authors.initials: L
authors.lastname: Lipfert
authors.forename: Kara
authors.initials: K
authors.lastname: Merkle
authors.forename: Brenda
authors.initials: B
authors.lastname: Pennypacker
authors.forename: Thomayant
authors.initials: T
authors.lastname: Prueksaritanont
authors.forename: Gideon A
authors.initials: GA
authors.lastname: Rodan
authors.forename: Gregg A
authors.initials: GA
authors.lastname: Wesolowski
authors.forename: Sevgi B
authors.initials: SB
authors.lastname: Rodan
authors.forename: Mark E
authors.initials: ME
authors.lastname: Duggan
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D015519:Bone Density / Q000187:drug effects; D001862:Bone Resorption / Q000188:drug therapy; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008253:Macaca mulatta; D008958:Models, Molecular; D009287:Naphthyridines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D010024:Osteoporosis / Q000188:drug therapy* / Q000517:prevention & control; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C492677:3-(methylpyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-(1,8)naphthyridin-2-yl)nonanoic acid; C492676:3-pyrimidin-5-yl-9-(5,6,7,8-tetrahydro-(1,8)naphthyridin-2-yl)nonanoic acid; D016023:Integrins; D009287:Naphthyridines; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5