Design and Characterization of Orally Active Arg-Gly-Asp Peptidomimetic Vitronectin Receptor Antagonist SB 265123 for Prevention of Bone Loss in Osteoporosis

The Arg-Gly-Asp (RGD)-binding integrin α V β 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 α v β 3 antagonist, SB 265123, which prevents bone loss in vivo when dosed by oral administration. SB 265123 binds α v β 3 and the closely related integrin α v β 5 with high affinity ( K i = 3.5 and 1.3 nM, respectively), but binds only weakly to the related RGD-binding integrins α IIb β 3 ( K i >1 μM) and α 5 β 1 ( K i >1 μM). The compound inhibits α v β 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 α v β 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.