Vol. 291, Issue 2, 612-617, November 1999

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

Michael W. Lark, George B. Stroup, Shing Mei Hwang, Ian E. James, David J. Rieman, Fred H. Drake, Jeremy N. Bradbeer, Ashwini Mathur, Karl F. Erhard, Kenneth A. Newlander, Stephen T. Ross, Kevin L. Salyers, Brian R. Smith, William H. Miller, William F. Huffman and Maxine Gowen

Departments of Bone and Cartilage Biology (M.W.L., G.B.S., S.M.H., I.E.J., D.J.R., F.H.D., J.N.B., M.G.), Medicinal Chemistry (K.F.E., K.A.N., S.T.R., W.H.M., W.H.F.), Statistical Sciences (A.M.), and Drug Metabolism and Pharmacokinetics (K.L.S., B.R.S), SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania

The Arg-Gly-Asp (RGD)-binding integrin _V3 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 _v3 antagonist, SB 265123, which prevents bone loss in vivo when dosed by oral administration. SB 265123 binds _v3 and the closely related integrin _v5 with high affinity (K_i = 3.5 and 1.3 nM, respectively), but binds only weakly to the related RGD-binding integrins _IIb3 (K_i >1 µM) and ₅₁ (K_i >1 µM). The compound inhibits _v3-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 _v3 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.