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  • Title: SAR of carbon-linked, 2-substituted purines: synthesis and characterization of AP23451 as a novel bone-targeted inhibitor of Src tyrosine kinase with in vivo anti-resorptive activity.
    Author: Shakespeare WC, Wang Y, Bohacek R, Keenan T, Sundaramoorthi R, Metcalf C, Dilauro A, Roeloffzen S, Liu S, Saltmarsh J, Paramanathan G, Dalgarno D, Narula S, Pradeepan S, van Schravendijk MR, Keats J, Ram M, Liou S, Adams S, Wardwell S, Bogus J, Iuliucci J, Weigele M, Xing L, Boyce B, Sawyer TK.
    Journal: Chem Biol Drug Des; 2008 Feb; 71(2):97-105. PubMed ID: 18179464.
    Abstract:
    Targeted disruption of the pp60(src) (Src) gene has implicated this tyrosine kinase in osteoclast-mediated bone resorption and as a therapeutic target for the treatment of osteoporosis and other bone-related diseases. Here, we describe structure activity relationships of a novel series of carbon-linked, 2-substituted purines that led to the identification of AP23451 as a potent inhibitor of Src tyrosine kinase with antiresorptive activity in vivo. AP23451 features the use of an arylphosphinylmethylphosphinic acid moiety which confers bone-targeting properties to the molecule, thereby increasing local concentrations of the inhibitor to actively resorbing osteoclasts at the bone interface. AP23451 exhibited an IC50 = 68 nm against Src kinase; an X-ray crystal structure of the molecule complexed with Src detailed the molecular interactions responsible for its Src inhibition. In vivo, AP23451 demonstrated a dose-dependent decrease in PTH-induced hypercalcemia. Moreover, AP23517, a structurally and biochemically similar molecule with comparable activity (IC50 = 73 nm) except devoid of the bone-targeting element, demonstrated significantly reduced in vivo efficacy, suggesting that Src activity was necessary but not sufficient for in vivo activity in this series of compounds.
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