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

  • J Med Chem. 2011 Oct 13;54(19):6734-50. doi: 10.1021/jm200629m.
Maria-Elena Theoclitou  1 ,  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
Affiliations
  • 1. Cancer & Infection Research Area, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom. [email protected]
PMID: 21899292 DOI: 10.1021/jm200629m
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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