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 alpha(v)beta(3) is highly expressed on osteoclasts and has been proposed to mediate cell-matrix adhesion requir ed for osteoclast-mediated bone resorption. Antagonism of this receptor sho uld prevent stable osteoclast adhesion and thereby inhibit bone resorption. We have generated an orally bioavailable, nonpeptide RGD mimetic alpha(v)b eta(3) antagonist, SB 265123, which prevents bone loss in vivo when dosed b y oral administration. SB 265123 binds alpha(v)beta(3) and the closely rela ted integrin alpha(v)beta(5) with high affinity (K-i = 3.5 and 1.3 nM, resp ectively), but binds only weakly to the related RGD-binding integrins alpha (IIb)beta(3) (K-i >1 mu M) and alpha(5)beta(1) (K-i >1 mu M). The compound inhibits alpha(v)beta(3)-mediated cell adhesion with an IC50 = 60 nM and mo re 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 dos ed 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 2 65123 prevents bone resorption in a dose-dependent fashion. This is the fir st report of an orally active alpha(v)beta(3) antagonist that is effective at inhibiting bone resorption when dosed in a pharmaceutically acceptable f ashion. Such a molecule may provide a novel therapeutic agent for the treat ment of postmenopausal osteoporosis.