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Discovery of (R)-8-(1-(3,5-Difluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (AZD8186): A Potent and Selective Inhibitor of PI3Kβ and PI3Kδ for the Treatment of PTEN-Deficient Cancers
- Source :
- Journal of Medicinal Chemistry. 58:943-962
- Publication Year :
- 2015
- Publisher :
- American Chemical Society (ACS), 2015.
-
Abstract
- Several studies have highlighted the dependency of PTEN deficient tumors to PI3Kβ activity and specific inhibition of PI3Kδ has been shown activity against human B-cell cancers. We describe the discovery and optimization of a series of 8-(1-anilino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamides as PI3Kβ/δ inhibitors, which led to the discovery of the clinical candidate 13, also known as AZD8186. On the basis of the lower lipophilicity of the chromen-4-one core compared to the previously utilized pyrido[1,2-a]pyrimid-4-one core, this series of compounds displayed high metabolic stability and suitable physical properties for oral administration. Compound 13 showed profound pharmacodynamic modulation of p-Akt in PTEN-deficient PC3 prostate tumor bearing mice after oral administration and showed complete inhibition of tumor growth in the mouse PTEN-deficient PC3 prostate tumor xenograft model. 13 was selected as a clinical candidate for treatment of PTEN-deficient cancers and has recently entered phase I clinical trials.
- Subjects :
- Male
Morpholino
medicine.drug_class
Carboxamide
Pharmacology
Mice
Structure-Activity Relationship
Dogs
Prostate
Oral administration
Drug Discovery
medicine
Animals
Humans
Structure–activity relationship
PTEN
Phosphoinositide-3 Kinase Inhibitors
Aniline Compounds
biology
Chemistry
Drug discovery
PTEN Phosphohydrolase
Neoplasms, Experimental
medicine.anatomical_structure
Chromones
Lipophilicity
biology.protein
Molecular Medicine
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 58
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....374fddcd264180d79fb9424642feb5b5