1403458-25-2

Upstream product

• 5382-16-1 4-HYDROXYPIPERIDINE 
• 1403458-61-6 methyl 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate 
• 1403458-59-2 tert-butyl 2-(6-(methoxycarbonyl)-2-morpholino-4-oxo-4H-chromen-8-yl)pyrrolidine-1-carboxylate 
• 1403458-58-1 tert-butyl 2-(6-(methoxycarbonyl)-2-morpholino-4-oxo-4H-chromen-8-yl)-1H-pyrrole-1-carboxylate 
• 1296271-33-4 methyl 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylate 

Relevant academic research and scientific papers

Discovery of a series of 8-(1-phenylpyrrolidin-2-yl)-6-carboxamide-2-morpholino-4H-chromen-4-one as PI3Kβ/δ inhibitors for the treatment of PTEN-deficient tumours

Attempts to lock the active conformation of compound 4, a PI3Kβ/δ inhibitor (PI3Kβ cell IC50 0.015?μM), led to the discovery of a series of 8-(1-phenylpyrrolidin-2-yl)-6-carboxamide-2-morpholino-4H-chromen-4-ones, which showed high levels of potency and selectivity as PI3Kβ/δ inhibitors. Compound 10 proved exquisitely potent and selective: PI3Kβ cell IC50 0.0011?μM in PTEN null MDA-MB-468 cell and PI3Kδ cell IC50 0.014?μM in Jeko-1 B-cell, and exhibited suitable physical properties for oral administration. In vivo, compound 10 showed profound pharmacodynamic modulation of AKT phosphorylation in a mouse PTEN-null PC3 prostate tumour xenograft after a single oral dose and gave excellent tumour growth inhibition in the same model after chronic oral dosing. Based on these results, compound 10 was selected as one of our PI3Kβ/δ preclinical candidates.