1421373-98-9

Basic information

• Product Name: AZ-5104
• Synonyms: AZ5104;AZ-5104;N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide;N-[2-[[2-(Dimethylamino)ethyl]methylamino]-5-[[4-(1H-indol-3-yl)-2-pyrimidinyl]amino]-4-methoxyphenyl]-2-propenamide;AZ7550;N-[2-(2-dimethylaminoethylmethylamino)-5-[[4-(1H-indol-3-yl)pyrimidin-2-yl]amino]-4-methoxyphenyl]prop-2-enamide;AZD5104
• CAS NO: 1421373-98-9
• Molecular Formula: C₂₇H₃₁N₇O₂
• Molecular Weight: 485.58074
• Product Categories: Inhibitors
• Mol File: 1421373-98-9.mol
• Article Data: 4

Chemical Properties

• Appearance: /
• Density: 1.267±0.06 g/cm3(Predicted)
• Storage Temp.: Refrigerator
• Solubility: Chloroform (Slightly), Methanol (Slightly)
• PKA: 12.68±0.70(Predicted)
• CAS DataBase Reference: AZ-5104(CAS DataBase Reference)
• NIST Chemistry Reference: AZ-5104(1421373-98-9)
• EPA Substance Registry System: AZ-5104(1421373-98-9)

Safety Data

• Hazardous Substances Data: 1421373-98-9(Hazardous Substances Data)

Usage

Uses

AZ7550 is an impurity of the drug Osimertinib (A808075). Osimertinib is a selective EGFR inhibitor (epidermal growth factor receptor), used in the treatments of nonsmall-cell lung cancer (NSCLC).

Biological Activity

az5104, is the demethylated metabolite of azd-9291,is a potent egfr inhibitor. ic50 <1 nm, 6 nm, 1 nm, 25 nm, for egfr (l858r/t790m), egfr (l858r), egfr (l861q), and egfr (wildtype), respectively.egfr (epidermal growth factor receptor) is a receptor tyrosine kinase on the cell surface. the receptor activation leads to dimerization and tyrosine autophosphorylation. it induces downstream cellular responses such as modification in gene expression, cell proliferation and cytoskeletal rearrangement etc.compare to azd9291, az5104 has somewhat more potency in mutant egfr cell lines ex19del (2 nmol/l in pc-9), t790m (2 nmol/l in h1975), and wild-type egfr (33 nmol/l in lovo) cell lines. in a phenotypic assay, az5104 showed a greater potency across cell lines in a phenotypic assay.3 hours after oral dosing in the mouse, the circulating active metabolites in plasma is 33% for az5104. in both c/l858r and c/l+t mice, 5 mg/kg/day dose of az5104, also show efficacy in shrinking tumors.

references

1. cross da, ashton se, ghiorghiu s et al. azd9291, an irreversible egfr tki, overcomes t790m-mediated resistance to egfr inhibitors in lung cancer. cancer discov. 2014 sep;4(9):1046-61.

Upstream product

• 1075705-01-9 4-fluoro-2-methoxy-5-nitro-phenylamine 
• 1421372-34-0 N- (4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine 
• 1421373-32-1 N₁-(4-(1H-indol-3-yl)pyrimidin-2-yl)-N₄-(2-(dimethylamino)ethyl)-2-methoxy-N₄-methyl-5-nitrobenzene-1,4-diamine 
• 450-91-9 4-fluoro-2-methoxyaniline 
• 1421373-31-0 N⁴-(4-(1H-indol-3-yl)pyrimidin-2-yl)-N¹-(2-(dimethylamino)ethyl)-5-methoxy-N¹-methylbenzene-1,2,4-triamine 

Relevant articles and documents

Alkynyl-containing AZD9291 derivative, preparation method and application thereof

The invention relates to an alkynyl-containing AZD9291 derivative, a preparation method and application thereof. The structural general formula (I) of the alkynyl-containing AZD9291 derivative is shown as the specification. Compared with the prior art, an AZD9291 analogue is synthesized and alkynyl is introduced, so that not only is the property of the AZD9291 analogue retained, but also the property of alkynyl is improved, the in-vitro antitumor activity is enhanced, and a good inhibition effect is achieved on a variety of tumor cells, and the alkynyl-containing AZD9291 derivative is an idealmedicine for treating diseases caused by EGFR mutation.

Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor

Epidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number of years. Despite encouraging clinical efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation. In addition, EGFR wild type receptor inhibition inherent with these agents can lead to dose limiting toxicities of rash and diarrhea. We describe herein the evolution of an early, mutant selective lead to the clinical candidate AZD9291, an irreversible inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations with selectivity over the wild type form of the receptor. Following observations of significant tumor inhibition in preclinical models, the clinical candidate was administered clinically to patients with T790M positive EGFR-TKI resistant NSCLC and early efficacy has been observed, accompanied by an encouraging safety profile.