Biological Activity
sb 273005 is a potent nonpeptide antagonist of αvβ3 (vitronectin receptor), with ki values of 1.2 nm and 0.3 nm to two closely related integrins, αvβ3 and αvβ5, respectively [1].αvβ3 belongs to the integrin family of adhesion molecules. it is a heterodimer. it mediates cell adhesion to serum proteins and extracellular matrix via the recognition of the arg-gly-asp (rgd) sequence [1].sb 273005 binds αvβ3 and αvβ5 with low nm affinity, but binds weakly to integrins αiibβ3 and α5β1. sb 273005 inhibits αvβ3-mediated cell adhesion with an ic50 value of 3 nm, endothelial cell migration with an ic50 of 1.8 nm, and osteoclast-mediated bone resorption with an ic50 of 11 nm in vitro [1].the αvβ3 integrin is pivotal in bone resorption [2]. in the chronic ovx and thyroparathyroidectomized bone resorption rat models, sb 273005 as well as other similar vitronectin receptor antagonists, inhibit bone loss. in aia rats, prophylactical treatment with sb 273005 at doses of 60, 30, and 10 mg/kg twice daily significantly normalized bone mineral density (bmd). normalization values of bmd were 69%, 42%, and 44% for doses of 60, 30, and 10 mg/kg twice daily, respectively. a single daily dose of sb 273005 significantly improved bmd (24% normalization) only when sb 273005 was prophylactically administered at 60 mg/kg [1].
in vitro
In rat models of bone resorption and osteoporosis, SB273005 (30 mg/kg, po) inhibits parathyroid hormone-stimulated calcium responses and inhibits bone loss. In adjuvant arthritis rats, it significantly reduced adjuvant-induced arthritis symptoms.
