1627494-13-6

Basic information

• Product Name: AZD8186
• Synonyms: AZD8186;AZD 8186, >=98%;(R)-8-(1-(3,5-difluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide;8-[(1R)-1-[(3,5-Difluorophenyl)amino]ethyl]-N,N-dimethyl-2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-6-carboxamide;EOS-61540
• CAS NO: 1627494-13-6
• Molecular Formula: C24H25F2N3O4
• Molecular Weight: 457.4698064
• EINECS: -0
• Mol File: 1627494-13-6.mol

Chemical Properties

• Boiling Point: 645.2±55.0 °C(Predicted)
• Appearance: /
• Density: 1.351±0.06 g/cm3(Predicted)
• Storage Temp.: -20°C Freezer
• Solubility: DMSO (Slightly), Ethanol (Slightly), Methanol (Slightly)
• PKA: 2.56±0.50(Predicted)
• CAS DataBase Reference: AZD8186(CAS DataBase Reference)
• NIST Chemistry Reference: AZD8186(1627494-13-6)
• EPA Substance Registry System: AZD8186(1627494-13-6)

Safety Data

• Hazardous Substances Data: 1627494-13-6(Hazardous Substances Data)

Usage

Uses

Used in Oncology:
AZD8186 is used as an anticancer agent for the treatment of PTEN-deficient cancers. It targets and inhibits the PI3Kβ and PI3Kδ enzymes, which are often overactive in these types of cancers, leading to uncontrolled cell growth and tumor development. By inhibiting these enzymes, AZD8186 can potentially slow down or stop the growth of cancer cells, providing a new therapeutic option for patients with PTEN-deficient cancers.
Additionally, AZD8186 may be used in combination with other cancer treatments, such as chemotherapy or radiation therapy, to enhance their effectiveness and improve patient outcomes. Further research and clinical trials are necessary to fully understand the potential benefits and limitations of AZD8186 in various cancer treatments.

Biological Activity

the pi3k-akt signaling pathway plays a critical role in cell growth, proliferation, motility, and survival. in human cancer, this pathway is activated by several mechanisms, including somatic mutations, deletions, and amplifications. class i pi3ks are further divided into class ia enzymes (pi3kα, pi3kβ, and pi3kδ) and class ib enzymes (pi3kγ). azd8186 is a potent and selective inhibitor of pi3kβ and pi3kδ.

in vitro

azd8186 gave potent inhibition of p-akt in cells sensitive to pi3kβ inhibition and in cells sensitive to pi3kδ inhibition but not to cells sensitive to pi3kα inhibition. the overall kinase selectivity of azd8186 was evaluated in several panels of recombinant protein and lipid kinase assays. 13 did not show significant activity against a panel of 59 protein kinases tested at 1 μm [1].

in vivo

the antitumor activity of azd8186 was evaluated in the pten deficient pc3 prostate tumor xenograft model in nude mice, either at 100 mg/kg b.i.d. without abt coadministration, or at 60, 30, and 10 mg/mg b.i.d. with abt coadministration. higher inhibition was seen in the 60 and 30 mg/kg groups with abt coadministration than in the 100 mg/kg group without abt coadministration [1].

IC 50

0.003 μm for pi3kβ and 0.017 μm for pi3kδ

Upstream product

• 1296271-49-2 8-(1-hydroxyethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide 
• 1296271-50-5 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide 
• 1296271-46-9 8-(1-hydroxyethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid 
• 1296271-40-3 methyl 8-(1-hydroxyethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate 
• 1296271-39-0 methyl 8-acetyl-2-morpholino-4-oxo-4H-chromene-6-carboxylate 
• 1296271-38-9 methyl 3-bromo-4-hydroxy-5-(3-morpholino-3-oxopropanoyl)benzoate 
• 62604-08-4 4-morpholinecarbodithioic acid methyl ester 
• 71407-98-2 3-acetyl-5-bromo-4-hydroxybenzoic acid 
• 149817-68-5 methyl 4-acetoxy-3-bromobenzoate 
• 1296271-33-4 methyl 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylate 
• 1296271-95-8 8-(1-(3,5-difluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide 
• 57009-12-8 methyl 3-acetyl-4-hydroxybenzoate 
• 160753-84-4 methyl 3-acetyl-5-bromo-4-hydroxybenzoate 
• 29415-97-2 methyl 3-bromo-4-hydroxybenzoate 

Relevant articles and documents

Development and Scale-Up of an Asymmetric Synthesis of AZD8186 Using the Fukuyama Modification of the Mitsunobu Reaction

A large-scale asymmetric synthesis has been developed for the kilo-lab manufacture of AZD8186. The process initially employs a regioselective Heck coupling in water to provide the starting aromatic ketone. This ketone is reduced asymmetrically under ruthenium-catalyzed transfer hydrogenation conditions to provide a chiral alcohol in high enantiomeric purity. The key synthetic step then requires the reaction of this chiral alcohol with the activated derivative of 3,5-difluoroaniline under the Mitsunobu reaction conditions. The common issues associated with the use of the Mitsunobu reaction, such as removal of triphenylphosphine oxide and reduced diisopropyl azodicarboxylate (DIAD) by-products, have been eliminated through crystallization of the relevant intermediates.

Discovery of (R)-8-(1-(3,5-difluorophenylamino)ethyl)- N, N -dimethyl-2-morpholino-4-oxo-4 H -chromene-6-carboxamide (AZD8186): A potent and selective inhibitor of PI3Kβ and PI3Kδ for the treatment of PTEN-deficient cancers

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.

CHROMENONE DERIVATIVES WITH ANTI-TUMOUR ACTIVITY

The invention concerns chromenone derivatives of Formula (I) or a pharmaceutically-acceptable salts thereof, wherein each of R1, R2, R3, R4, R5, R6, R7, R8, n and R9 has any of the meanings defined hereinbefore in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use in the treatment of cell proliferative disorders.

CHROMENONE DERIVATIVES

The invention concerns chromenone derivatives of Formula I or a pharmaceutically-acceptable salts thereof, wherein each of R1, R2, R3, R4, R5, R6, R7, R8, n and R9 has any of the meanings defined hereinbefore in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use in the treatment of cell proliferative disorders.