1. 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.
- Author
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Theoclitou ME, Aquila B, Block MH, Brassil PJ, Castriotta L, Code E, Collins MP, Davies AM, Deegan T, Ezhuthachan J, Filla S, Freed E, Hu H, Huszar D, Jayaraman M, Lawson D, Lewis PM, Nadella MV, Oza V, Padmanilayam M, Pontz T, Ronco L, Russell D, Whitston D, and Zheng X
- Subjects
- Animals, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Benzamides pharmacokinetics, Benzamides pharmacology, Blood Proteins metabolism, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Drug Screening Assays, Antitumor, Hepatocytes metabolism, Humans, M Phase Cell Cycle Checkpoints drug effects, Mice, Mice, Nude, Microsomes, Liver metabolism, Protein Binding, Pyrimidinones pharmacokinetics, Pyrimidinones pharmacology, Rats, Rats, Wistar, Solubility, Stereoisomerism, Structure-Activity Relationship, Antineoplastic Agents chemical synthesis, Benzamides chemical synthesis, Kinesins antagonists & inhibitors, Pyrimidinones chemical synthesis
- 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.
- Published
- 2011
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