title: Nonpeptide alpha V beta 3 antagonists. Part 10: In vitro and in vivo evaluation of a potent 7-methyl substituted tetrahydro-[1,8]naphthyridine derivative.
abstract: Subtle modifications were incorporated into the structure of clinical candidate 1. These changes were designed to maintain potency and selectivity while inducing changes in physical properties leading to improved pharmacokinetics in three species. This approach led to the identification of 4 as a potent, selective alphaVbeta3 receptor antagonist that was selected for clinical development based on an improved PK profile and efficacy demonstrated in an in vivo model of bone turnover.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. michael_breslin@merck.com
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Breslin
authors.forename: Mark E
authors.initials: ME
authors.lastname: Duggan
authors.forename: Wasyl
authors.initials: W
authors.lastname: Halczenko
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
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: Donald B
authors.initials: DB
authors.lastname: Kimmel
authors.forename: Chih-Tai
authors.initials: CT
authors.lastname: Leu
authors.forename: Kara
authors.initials: K
authors.lastname: Merkle
authors.forename: Thomayant
authors.initials: T
authors.lastname: Prueksaritanont
authors.forename: Gideon A
authors.initials: GA
authors.lastname: Rodan
authors.forename: Sevgi B
authors.initials: SB
authors.lastname: Rodan
authors.forename: John H
authors.initials: JH
authors.lastname: Hutchinson
mesh_terms: D000818:Animals; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D009287:Naphthyridines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats
chemical_list: D039302:Integrin alphaVbeta3; D009287:Naphthyridines