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.

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.

• Authors: William C Shakespeare, Yihan Wang, Regine Bohacek, Terry Keenan, Raji Sundaramoorthi, Chet Metcalf 3rd, Anne Dilauro, Sonya Roeloffzen, Shuangying Liu, Jennifer Saltmarsh, Guru Paramanathan, David Dalgarno, Surinder Narula, Selvi Pradeepan, Marie Rose van Schravendijk, Jeff Keats, Mary Ram, Shuenn Liou, Susan Adams, Scott Wardwell, Julie Bogus, John Iuliucci, Manfred Weigele, Lianping Xing, Brendan Boyce, Tomi K Sawyer
• Journal: Chemical biology & drug design (Chem Biol Drug Des) Vol. 71 Issue 2 Pg. 97-105 (Feb 2008) ISSN: 1747-0285 [Electronic] England
• PMID: 18179464 (Publication Type: Journal Article)

Chemical References

• AP 23451
• Enzyme Inhibitors
• Organophosphonates
• Parathyroid Hormone
• Phosphinic Acids
• Purines
• src-Family Kinases
• Adenine

Topics

• Adenine (analogs & derivatives, chemistry, pharmacology)
• Bone Resorption (drug therapy)
• Crystallography, X-Ray
• Drug Delivery Systems
• Enzyme Inhibitors (chemistry, pharmacology)
• Humans
• Hypercalcemia
• Inhibitory Concentration 50
• Molecular Structure
• Organophosphonates (chemistry, pharmacology)
• Osteoporosis (drug therapy)
• Parathyroid Hormone (pharmacology)
• Phosphinic Acids
• Purines (chemical synthesis, pharmacology)
• Structure-Activity Relationship
• src-Family Kinases (antagonists & inhibitors, chemistry)