title: Design and characterization of orally active Arg-Gly-Asp peptidomimetic vitronectin receptor antagonist SB 265123 for prevention of bone loss in osteoporosis.
abstract: The Arg-Gly-Asp (RGD)-binding integrin alpha(V)beta(3) is highly expressed on osteoclasts and has been proposed to mediate cell-matrix adhesion required for osteoclast-mediated bone resorption. Antagonism of this receptor should prevent stable osteoclast adhesion and thereby inhibit bone resorption. We have generated an orally bioavailable, nonpeptide RGD mimetic alpha(v)beta(3) antagonist, SB 265123, which prevents bone loss in vivo when dosed by oral administration. SB 265123 binds alpha(v)beta(3) and the closely related integrin alpha(v)beta(5) with high affinity (K(i) = 3.5 and 1.3 nM, respectively), but binds only weakly to the related RGD-binding integrins alpha(IIb)beta(3) (K(i) >1 microM) and alpha(5)beta(1) (K(i) >1 microM). The compound inhibits alpha(v)beta(3)-mediated cell adhesion with an IC(50) = 60 nM and more importantly, inhibits human osteoclast-mediated bone resorption in vitro with an IC(50) = 48 nM. In vivo, SB 265123 completely blocks bone resorption in a thyroparathyroidectomized rat model of acute bone resorption when dosed at 2.5 mg/kg/h by continuous i.v. infusion. When dosed orally with 3 to 30 mg/kg b.i.d. , in the ovariectomy-induced rat model of osteoporosis, SB 265123 prevents bone resorption in a dose-dependent fashion. This is the first report of an orally active alpha(v)beta(3) antagonist that is effective at inhibiting bone resorption when dosed in a pharmaceutically acceptable fashion. Such a molecule may provide a novel therapeutic agent for the treatment of postmenopausal osteoporosis.
authors.affiliation: Department of Bone and Cartilage Biology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, USA. michael__lark1@sbphrd.com
authors.forename: M W
authors.initials: MW
authors.lastname: Lark
authors.forename: G B
authors.initials: GB
authors.lastname: Stroup
authors.forename: S M
authors.initials: SM
authors.lastname: Hwang
authors.forename: I E
authors.initials: IE
authors.lastname: James
authors.forename: D J
authors.initials: DJ
authors.lastname: Rieman
authors.forename: F H
authors.initials: FH
authors.lastname: Drake
authors.forename: J N
authors.initials: JN
authors.lastname: Bradbeer
authors.forename: A
authors.initials: A
authors.lastname: Mathur
authors.forename: K F
authors.initials: KF
authors.lastname: Erhard
authors.forename: K A
authors.initials: KA
authors.lastname: Newlander
authors.forename: S T
authors.initials: ST
authors.lastname: Ross
authors.forename: K L
authors.initials: KL
authors.lastname: Salyers
authors.forename: B R
authors.initials: BR
authors.lastname: Smith
authors.forename: W H
authors.initials: WH
authors.lastname: Miller
authors.forename: W F
authors.initials: WF
authors.lastname: Huffman
authors.forename: M
authors.initials: M
authors.lastname: Gowen
mesh_terms: D000085:Acetates / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D000284:Administration, Oral; D000631:Aminopyridines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001862:Bone Resorption / Q000517:prevention & control*; D002448:Cell Adhesion / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D016023:Integrins / Q000378:metabolism; D010024:Osteoporosis / Q000517:prevention & control; D010052:Ovariectomy; D016105:Parathyroidectomy; D010974:Platelet Aggregation / Q000187:drug effects*; D011485:Protein Binding; D051381:Rats; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors*; D013965:Thyroidectomy; D013997:Time Factors
chemical_list: D000085:Acetates; D000631:Aminopyridines; D016023:Integrins; D019030:Receptors, Vitronectin; C121647:SB 265123