Abstract

The Arg-Gly-Asp (RGD)-binding integrin α_Vβ₃is 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_vβ₃antagonist, SB 265123, which prevents bone loss in vivo when dosed by oral administration. SB 265123 binds α_vβ₃and the closely related integrin α_vβ₅ with high affinity (K_i = 3.5 and 1.3 nM, respectively), but binds only weakly to the related RGD-binding integrins α_IIbβ₃(K_i >1 μM) and α₅β₁ (K_i >1 μM). The compound inhibits α_vβ₃-mediated cell adhesion with an IC₅₀ = 60 nM and more importantly, inhibits human osteoclast-mediated bone resorption in vitro with an IC₅₀ = 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_vβ₃ 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.