Discovery of (+)-N-(3-Aminopropyl)-N-[1-(5-benzyl-3-methyl-4-oxo-[1,2]thiazolo[5,4-d]pyrimidin-6-yl)-2-methylpropyl]-4-methylbenzamide (AZD4877), a Kinesin Spindle Protein Inhibit

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• 作者：Maria-Elena Theoclitou ; Brian Aquila ; Michael H. Block ; Patrick J. Brassil ; Lillian Castriotta ; Erin Code ; Michael P. Collins ; Audrey M. Davies ; Tracy Deegan ; Jayachandran Ezhuthachan ; Sandra Filla ; Ellen Freed ; Haiqing Hu ; Dennis Huszar ; Muthusamy Jayaraman ; Deborah Lawson ; Paula M Lewis ; Murali V. P. Nadella ; Vibha Oza ; Maniyan Padmanilayam ; Timothy Pontz ; Lucienne Ronco ; Daniel Russell ; David Whitston ; Xiaolan Zheng
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：October 13, 2011
• 年：2011
• 卷：54
• 期：19
• 页码：6734-6750
• 全文大小：1324K
• 年卷期：v.54,no.19(October 13, 2011)
• ISSN：1520-4804

文摘

Structure鈥揳ctivity relationship analysis identified (+)-N-(3-aminopropyl)-N-[1-(5-benzyl-3-methyl-4-oxo-[1,2]thiazolo[5,4-d]pyrimidin-6-yl)-2-methylpropyl]-4-methylbenzamide (AZD4877), from a series of novel kinesin spindle protein (KSP) inhibitors, as exhibiting both excellent biochemical potency and pharmaceutical properties suitable for clinical development. The selected compound arrested cells in mitosis leading to the formation of the monopolar spindle phenotype characteristic of KSP inhibition and induction of cellular death. A favorable pharmacokinetic profile and notable in vivo efficacy supported the selection of this compound as a clinical candidate for the treatment of cancer.