Pyrido[2,3-d]pyrimidin-5-ones: A Novel Class of Antiinflammatory Macrophage Colony-Stimulating Factor-1 Receptor Inhibitors†

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• 作者：Hui Huang ; Daniel A. Hutta ; James M. Rinker ; Huaping Hu ; William H. Parsons ; Carsten Schubert ; Renee L. DesJarlais ; Carl S. Crysler ; Margery A. Chaikin ; Robert R. Donatelli ; Yanmin Chen ; Deping Cheng
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：February 26, 2009
• 年：2009
• 卷：52
• 期：4
• 页码：1081-1099
• 全文大小：493K
• 年卷期：v.52,no.4(February 26, 2009)
• ISSN：1520-4804

文摘

A series of pyrido[2,3-d]pyrimidin-5-ones has been synthesized and evaluated as inhibitors of the kinase domain of macrophage colony-stimulating factor-1 receptor (FMS). FMS inhibitors may be useful in treating rheumatoid arthritis and other chronic inflammatory diseases. Structure-based optimization of the lead amide analogue 10 led to hydroxamate analogue 37, which possessed excellent potency and an improved pharmacokinetic profile. During the chronic phase of streptococcal cell wall-induced arthritis in rats, compound 37 (10, 3, and 1 mg/kg) was highly effective at reversing established joint swelling. In an adjuvant-induced arthritis model in rats, 37 prevented joint swelling partially at 10 mg/kg. In this model, osteoclastogenesis and bone erosion were prevented by low doses (1 or 0.33 mg/kg) that had minimal impact on inflammation. These data underscore the potential of FMS inhibitors to prevent erosions and reduce symptoms in rheumatoid arthritis.