Bone-targeted Src kinase inhibitors: novel pyrrolo- and pyrazolopyrimidine analogues.

Abstract

Src tyrosine kinase is a therapeutic target for bone diseases that has been validated by gene knockout studies. Furthermore, in vitro cellular studies implicate that Src has a positive regulatory role in osteoclasts and a negative regulatory role in osteoblasts. The potential use of Src inhibitors for osteoporosis therapy has been previously shown by novel bone-targeted ligands of the Src SH2 (e.g., AP22408) and non-bone-targeted, ATP-based inhibitors of Src kinase. Significant to this study, compounds 2-12 exemplify novel analogues of known pyrrolopyrimidine and pyrazolopyrimidine template-based Src kinase inhibitors that incorporate bone-targeting group modifications designed to provide tissue (bone) selectivity and diminished side effects. Accordingly, we report here the structure-based design, synthetic chemistry and biological testing of these compounds and proof-of-concept studies thereof.

• Authors: Raji Sundaramoorthi, William C Shakespeare, Terence P Keenan, Chester A Metcalf 3rd, Yihan Wang, Ukti Mani, Merry Taylor, Shuangying Liu, Regine S Bohacek, Surinder S Narula, David C Dalgarno, Marie Rose van Schravandijk, Sheila M Violette, Shuenn Liou, Susan Adams, Mary K Ram, Jeffrey A Keats, Manfred Weigle, Tomi K Sawyer, Manfred Weigele
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 13 Issue 18 Pg. 3063-6 (Sep 15 2003) ISSN: 0960-894X [Print] England
• PMID: 12941334 (Publication Type: Journal Article)

Chemical References

• Enzyme Inhibitors
• Purines
• Pyrimidines
• Adenosine Triphosphate
• src-Family Kinases

Topics

• Adenosine Triphosphate (analogs & derivatives)
• Animals
• Bone Diseases (drug therapy)
• Drug Design
• Enzyme Inhibitors (chemical synthesis, pharmacology)
• Humans
• Inhibitory Concentration 50
• Models, Molecular
• Osteoporosis (drug therapy)
• Purines (chemical synthesis, pharmacology)
• Pyrimidines (chemical synthesis, pharmacology)
• Structure-Activity Relationship
• src-Family Kinases (antagonists & inhibitors)