Antagonism of the Osteoclast Vitronectin Receptor with an Orally Active Nonpeptide Inhibitor Prevents Cancellous Bone Loss in the Ovariectomized Rat

An orally active, nonpeptide Arg‐Gly‐Asp (RGD) mimetic αvβ3 antagonist, (S)‐3‐Oxo‐8‐[2‐[6‐(methylamino)pyridin‐2‐yl]‐1‐ethoxy]‐2‐(2,2,2‐trifluoroethyl)‐2,3,4,5‐tetrahydro‐1H‐2‐benzazepine‐4‐acetic acid (compound 1), has been generated, which prevented net bone loss and inhibited cancellous bone turn...

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Published in:Journal of bone and mineral research 2001-02, Vol.16 (2), p.319-327
Main Authors: Lark, Michael W., Stroup, George B., Dodds, Robert A., Kapadia, Rasesh, Hoffman, Sandra J., Hwang, Shing Mei, James, Ian E., Lechowska, Beata, Liang, Xiaoguang, Rieman, David J., Salyers, Kevin L., Ward, Keith, Smith, Brian R., Miller, William H., Huffman, William F., Gowen, Maxine
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
bone resorption
Bone Resorption - prevention & control
Diseases of the osteoarticular system
Female
integrins
Medical sciences
osteoclast
Osteoclasts - drug effects
Osteoclasts - metabolism
Osteoporosis. Osteomalacia. Paget disease
Ovariectomy
Pyridines - pharmacokinetics
Pyridines - pharmacology
Rats
Rats, Sprague-Dawley
Receptors, Vitronectin - antagonists & inhibitors
Vitronectin receptors
αvβ3
αvβ5
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Summary:An orally active, nonpeptide Arg‐Gly‐Asp (RGD) mimetic αvβ3 antagonist, (S)‐3‐Oxo‐8‐[2‐[6‐(methylamino)pyridin‐2‐yl]‐1‐ethoxy]‐2‐(2,2,2‐trifluoroethyl)‐2,3,4,5‐tetrahydro‐1H‐2‐benzazepine‐4‐acetic acid (compound 1), has been generated, which prevented net bone loss and inhibited cancellous bone turnover in vivo. The compound binds αvβ3 and the closely related integrin αvβ5 with low nanomolar affinity but binds only weakly to the related integrins αIIbβ3, and α5β1. Compound 1 inhibited αvβ3‐mediated cell adhesion with an IC50 = 3 nM. More importantly, the compound inhibited human osteoclast‐mediated bone resorption in vitro with an IC50 = 11 nM. In vivo, compound 1 inhibited bone resorption in a dose‐dependent fashion, in the acute thyroparathyroidectomized (TPTX) rat model of bone resorption with a circulating EC50 ∼ 20 μM. When dosed orally at 30 mg/kg twice a day (b.i.d.) in the chronic ovariectomy (OVX)‐induced rat model of osteopenia, compound 1 also prevented bone loss. At doses ranging from 3 to 30 mg/kg b.i.d., compound 1 partially prevented the OVX‐induced increase in urinary deoxypyridinoline. In addition, the compound prevented the OVX‐induced reduction in cancellous bone volume (BV), trabecular number (Tb.N), and trabecular thickness (Tb.Th), as assessed by quantitative microcomputerized tomography (μCT) and static histomorphometry. Furthermore, both the 10‐mg/kg and 30‐mg/kg doses of compound prevented the OVX‐induced increase in bone turnover, as measured by percent osteoid perimeter (%O.Pm). Together, these data indicate that the αVβ3 antagonist compound 1 inhibits OVX‐induced bone loss. Mechanistically, compound 1 prevents bone loss in vivo by inhibiting osteoclast‐mediated bone resorption, ultimately preventing cancellous bone turnover.
ISSN:0884-0431
1523-4681
DOI:10.1359/jbmr.2001.16.2.319