title: Nonpeptide alpha(v)beta(3) antagonists. 1. Transformation of a potent, integrin-selective alpha(IIb)beta(3) antagonist into a potent alpha(v)beta(3) antagonist.
abstract: Modification of the potent fibrinogen receptor (alpha(IIb)beta(3)) antagonist 1 generated compounds with high affinity for the vitronectin receptor alpha(v)beta(3). Sequential modification of the basic N-terminus of 1 led to the identification of the 5,6,7, 8-tetrahydro[1,8]naphthyridine moiety (THN) as a lipophilic, moderately basic N-terminus that provides molecules with excellent potency and selectivity for the integrin receptor alpha(v)beta(3). The THN-containing analogue 5 is a potent inhibitor of bone resorption in vitro and in vivo. In addition, the identification of a novel, nonpeptide radioligand with high affinity to alpha(v)beta(3) is also reported.
authors.affiliation: Departments of Medicinal Chemistry, Bone Biology and Osteoporosis Research, and Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Duggan
authors.forename: L T
authors.initials: LT
authors.lastname: Duong
authors.forename: J E
authors.initials: JE
authors.lastname: Fisher
authors.forename: T G
authors.initials: TG
authors.lastname: Hamill
authors.forename: W F
authors.initials: WF
authors.lastname: Hoffman
authors.forename: J R
authors.initials: JR
authors.lastname: Huff
authors.forename: N C
authors.initials: NC
authors.lastname: Ihle
authors.forename: C T
authors.initials: CT
authors.lastname: Leu
authors.forename: R M
authors.initials: RM
authors.lastname: Nagy
authors.forename: J J
authors.initials: JJ
authors.lastname: Perkins
authors.forename: S B
authors.initials: SB
authors.lastname: Rodan
authors.forename: G
authors.initials: G
authors.lastname: Wesolowski
authors.forename: D B
authors.initials: DB
authors.lastname: Whitman
authors.forename: A E
authors.initials: AE
authors.lastname: Zartman
authors.forename: G A
authors.initials: GA
authors.lastname: Rodan
authors.forename: G D
authors.initials: GD
authors.lastname: Hartman
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000473:pathology; D002460:Cell Line; D046508:Culture Techniques; D006801:Humans; D008024:Ligands; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C415162:2-benzenesulfonylamino-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)benzoylamino)propionic acid; D008024:Ligands; D009287:Naphthyridines; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011422:Propionates; D013449:Sulfonamides