Abstract
The Arg-Gly-Asp (RGD)-binding integrin αVβ3is 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 αvβ3antagonist, SB 265123, which prevents bone loss in vivo when dosed by oral administration. SB 265123 binds αvβ3and the closely related integrin αvβ5 with high affinity (Ki = 3.5 and 1.3 nM, respectively), but binds only weakly to the related RGD-binding integrins αIIbβ3(Ki >1 μM) and α5β1 (Ki >1 μM). The compound inhibits αvβ3-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 αvβ3 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.
Footnotes
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Send reprint requests to: Michael W. Lark, UW2109, SmithKline Beecham Pharmaceuticals, 709 Swedeland Rd., King of Prussia, PA. E-mail: michael_lark-1{at}sbphrd.com
- Abbreviations:
- TPTX
- thyroparathyroidectomized
- ovx
- ovariectomized
- PTH
- parathyroid hormone
- BMD
- bone mineral density
- Received April 27, 1999.
- Accepted June 22, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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