1620576-64-8

Basic information

• Product Name: 1-(4-(5-(5-amino-6-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-hydroxypropan-1-one
• Synonyms: 1-(4-(5-(5-amino-6-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-hydroxypropan-1-one;AZD-8835
• CAS NO: 1620576-64-8
• Molecular Formula: C22H31N9O3
• Molecular Weight: 469.54004
• EINECS: -0
• Mol File: 1620576-64-8.mol
• Article Data: 4

Chemical Properties

• Boiling Point: 784.0±70.0 °C(Predicted)
• Appearance: /
• Density: 1.45±0.1 g/cm3(Predicted)
• Solubility: Soluble in DMSO
• PKA: 14.68±0.10(Predicted)
• CAS DataBase Reference: 1-(4-(5-(5-amino-6-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-hydroxypropan-1-one(CAS DataBase Reference)
• NIST Chemistry Reference: 1-(4-(5-(5-amino-6-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-hydroxypropan-1-one(1620576-64-8)
• EPA Substance Registry System: 1-(4-(5-(5-amino-6-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-hydroxypropan-1-one(1620576-64-8)

Safety Data

• Hazardous Substances Data: 1620576-64-8(Hazardous Substances Data)

Usage

Biological Activity

azd8835 is a dual pi3kα and pi3kδ inhibitor.the pik3ca gene, encoding the p110α catalytic unit of pi3kα, is one of the most mutated oncogenes in human cancer. therefore, pi3kα is a critical target in identifying inhibitors and testing their therapeutic application.

in vitro

azd8835 was identified as a potent dual inhibitor of pi3kα and pi3kδ with good selectivity versus pi3kβ, pi3kγ, as well as other kinases that readily inhibited cell growth with mutant pik3ca status, such as in estrogen receptor-positive breast cancer cell lines including mcf7, bt474, and t47d [1].

in vivo

previous animal study demonstrated that azd8835 had antitumor efficacy in breast cancer xenograft models when azd8835 was continuously dosed. in addition, the monotherapy of azd8835 was found to be able to induce tumor xenograft regression by using intermittent high-dose scheduling (ihds). furthermore, azd8835 ihds treatment in combination with other targeted therapeutic agents could further enhance its antitumor activity by up to 92% regression [1].

IC 50

6.2 and 5.7 nm for pi3kα and pi3kδ, respectively

references

[1] hudson k et al. intermittent high-dose scheduling of azd8835, a novel selective inhibitor of pi3kα and pi3kδ, demonstrates treatment strategies for pik3ca-dependent breast cancers. mol cancer ther.2016 may;15(5):877-89.

Upstream product

• 1225062-23-6 3-amino-6-bromopyrazine-2-carbohydrazide 
• 6966-01-4 methyl 3-amino-6-bromopyrazine-2-carboxylate 
• 1620583-34-7 (Z)-tert-butyl 4-(2-(amino(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)methylene)hydrazinecarbonyl)piperidine-1-carboxylate 
• 1620576-80-8 3-amino-6-bromo-N'-pivaloylpyrazine-2-carbohydrazide 
• 1620576-78-4 5-bromo-3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine 
• 1620576-77-3 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine 
• 6761-52-0 3-amino-pyrazine-2-carbohydrazide 
• 16298-03-6 Methyl 3-amino-2-pyrazinecarboxylate 
• 1620576-85-3 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-(1-ethyl-3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl)pyrazin-2-amine 
• 1639042-85-5 tert-butyl 4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate 
• 1620576-86-4 1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(tetrahydro-2H-pyran-2-yloxy)propan-1-one 
• 1620576-82-0 tert-butyl 4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate 
• 1620583-33-6 (Z)-5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazine-2-carbohydrazonamide 
• 1620576-81-9 5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazine-2-carbonitrile 

Relevant articles and documents

Discovery of 1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1,2,4-triazol-3-yl)piperidin-1-yl)-3-hydroxypropan-1-one (AZD8835): A potent and selective inhibitor of PI3Kα and PI3Kδ for the treatment of cancers

Starting from potent inhibitors of PI3Kα having poor general kinase selectivity (e.g., 1 and 2), optimisation of this series led to the identification of 25, a potent inhibitor of PI3Kα (wild type, E545K and H1047R mutations) and PI3Kδ, selective versus PI3Kβ and PI3Kγ, with excellent general kinase selectivity. Compound 25 displayed low metabolic turnover and suitable physical properties for oral administration. In vivo, compound 25 showed pharmacodynamic modulation of AKT phosphorylation and near complete inhibition of tumour growth (93% tumour growth inhibition) in a murine H1047R PI3Kα mutated SKOV-3 xenograft tumour model after chronic oral administration at 25 mg/kg b.i.d. Compound 25, also known as AZD8835, is currently in phase I clinical trials.

CHEMICAL COMPOUNDS

The invention concerns compounds of Formula (I) or pharmaceutically-acceptable salts thereof, wherein R1 to R5 have any of the meanings defined hereinbefore in the description: processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of cell proliferative disorders.