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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.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2011 Oct 13; Vol. 54 (19), pp. 6734-50. Date of Electronic Publication: 2011 Sep 07. - Publication Year :
- 2011
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 54
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 21899292
- Full Text :
- https://doi.org/10.1021/jm200629m