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 Inhibitor and Potential Anticancer Agent
Journal of Medicinal Chemistry2011Vol. 54(19), pp. 6734–6750
Citations Over TimeTop 19% of 2011 papers
Maria‐Elena Theoclitou, Brian Aquila, M. Block, Patrick Brassil, Lillian Castriotta, Erin Code, Michael P. Collins, Audrey M. Davies, Tracy L. Deegan, Ezhuthachan Jayachandran, Sandra Filla, Ellen Freed, Haiqing Hu, Dennis Huszar, Muthusamy Jayaraman, Deborah Lawson, Paula Lewis, Murali V.P. Nadella, Vibha Oza, Maniyan P. Padmanilayam, Timothy Pontz, Lucienne Ronco, Daniel Russell, David Whitston, Xiaolan Zheng
Abstract
Structure–activity 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.
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