Design, Synthesis, and Anaplastic Lymphoma Kinase (ALK) Inhibitory Activity for a Novel Series of 2,4,8,22-Tetraazatetracyclo[14.3.1.13,7.19,13]docosa-1(20),3(22),4,6,9(21),10,12

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• 作者：Henry J. Breslin ; Brandon M. Lane ; Gregory R. Ott ; Arup K. Ghose ; Thelma S. Angeles ; Mark S. Albom ; Mangeng Cheng ; Weihua Wan ; R. Curtis Haltiwanger ; Kevin J. Wells-Knecht ; Bruce D. Dorsey
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：January 12, 2012
• 年：2012
• 卷：55
• 期：1
• 页码：449-464
• 全文大小：573K
• 年卷期：v.55,no.1(January 12, 2012)
• ISSN：1520-4804

文摘

A novel set of 2,4,8,22-tetraazatetracyclo[14.3.1.1^3,7.1^9,13]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene macrocycles were prepared as potential anaplastic lymphoma kinase (ALK) inhibitors, designed to rigidly lock an energy-minimized bioactive conformation of the diaminopyrimidine (DAP) scaffold, a well-documented kinase platform. From 13 analogues prepared, macrocycle 2m showed the most promising in vitro ALK enzymatic (IC₅₀ = 0.5 nM) and cellular (IC₅₀ = 10 nM) activities. In addition, macrocycle 2m exhibited a favorable kinase selectivity preference for inhibition of ALK relative to the highly homologous insulin receptor (IR) kinase (IR/ALK ratio of 173). The inclusive in vitro biological results for this set of macrocycles validate this scaffold as a viable kinase template and further corroborate recent DAP/ALK solid state studies indicating that the inverted 鈥淯鈥?shaped conformation of the acyclic DAPs is a preferred bioactive conformation.