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
| العنوان: | 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 |
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| المؤلفون: | Selvi Pradeepan, Chet Metcalf, Brendan F. Boyce, Shuangying Liu, Manfred Weigele, Surinder S. Narula, Regine S. Bohacek, Lianping Xing, Raji Sundaramoorthi, Jeff Keats, Julie Bogus, Jennifer Saltmarsh, Yihan Wang, Scott Wardwell, Mary K. Ram, David C. Dalgarno, John Iuliucci, Susan Adams, Guru Paramanathan, Shuenn Liou, Marie Rose van Schravendijk, Anne Dilauro, Sonya Roeloffzen, T. Keenan, William C. Shakespeare, Tomi K. Sawyer |
| المصدر: | Chemical Biology & Drug Design. 71:97-105 |
| بيانات النشر: | Wiley, 2008. |
| سنة النشر: | 2008 |
| مصطلحات موضوعية: | Organophosphonates, Crystallography, X-Ray, Biochemistry, Bone resorption, Inhibitory Concentration 50, Structure-Activity Relationship, Drug Delivery Systems, In vivo, Drug Discovery, Humans, Structure–activity relationship, Bone Resorption, Enzyme Inhibitors, Purine metabolism, IC50, Pharmacology, Tyrosine-protein kinase CSK, Molecular Structure, Chemistry, Adenine, Organic Chemistry, Phosphinic Acids, src-Family Kinases, Parathyroid Hormone, Purines, Hypercalcemia, Osteoporosis, Molecular Medicine, Tyrosine kinase, Proto-oncogene tyrosine-protein kinase Src |
| الوصف: | 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. |
| تدمد: | 1747-0285 1747-0277 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9dcdeae0a92758c4ad04f2c1f5760a13 https://doi.org/10.1111/j.1747-0285.2007.00615.x |
| حقوق: | CLOSED |
| رقم الأكسشن: | edsair.doi.dedup.....9dcdeae0a92758c4ad04f2c1f5760a13 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17470285 17470277 |
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