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Antagonism of the Osteoclast Vitronectin Receptor with an Orally Active Nonpeptide Inhibitor Prevents Cancellous Bone Loss in the Ovariectomized Rat
Author(s) -
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
Publication year - 2001
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.2001.16.2.319
Subject(s) - osteoclast , ovariectomized rat , bone resorption , chemistry , in vivo , endocrinology , medicine , cancellous bone , deoxypyridinoline , osteopenia , bone remodeling , antagonist , resorption , osteoporosis , pharmacology , receptor , biochemistry , bone mineral , biology , osteocalcin , estrogen , anatomy , alkaline phosphatase , microbiology and biotechnology , enzyme
An orally active, nonpeptide Arg‐Gly‐Asp (RGD) mimetic α v β 3 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 α v β 3 and the closely related integrin α v β 5 with low nanomolar affinity but binds only weakly to the related integrins α IIb β 3 , and α 5 β 1 . Compound 1 inhibited α v β 3 ‐mediated cell adhesion with an IC 50 = 3 nM. More importantly, the compound inhibited human osteoclast‐mediated bone resorption in vitro with an IC 50 = 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 EC 50 ∼ 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 α V β 3 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.