AZ-5104

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.

Synthesis

1421373-31-0

814-68-6

1421373-98-9

GENERAL STEPS: A solution of acryloyl chloride (0.584 mL, 1 M in CH2Cl2, 0.58 mmol) was added slowly and dropwise to a solution of N1-(2-dimethylaminoethyl)-N4-[4-(1H-indol-3-yl)pyrimidin-2-yl]-5-methoxy-N1-methylbenzene-1,2,4-triamine (Intermediate 168, 252 mg, 0.58 mmol ) in a solution of CH2Cl2 (10 mL) and the reaction mixture was stirred at -5°C for 1 hour. Subsequently, the reaction mixture was diluted with CH2Cl2 (100 mL) and washed sequentially with saturated aqueous NaHCO3 solution (25 mL), water (25 mL) and saturated brine (25 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by fast column chromatography (FCC) using a gradient elution with CH2Cl2 solution of 0-30% CH3OH afforded the target compound N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (76 mg, 27% yield) as a white solid.1H NMR (CDCl3) δ: 2.25 (6H, s), 2.27-2.34 (3H, m), 2.69 (3H, s), 2.84-2.94 (2H, m), 3.87 (3H, s), 5.68 (1H, dd), 6.40 (1H, d), 6.48 (1H, dd), 6.78 (1H, s), 7.03 (1H, d). 7.03 (1H, d), 7.08-7.20 (2H, m), 7.33 (1H, dd), 7.65 (1H, s), 8.12 (1H, d), 8.26 (1H, d), 8.59 (1H, s), 9.74 (1H, s), 9.97 (1H, s), 10.24 (1H, s); m/z: ES+ [M+H]+ 486.

in vivo

IC 50

EGFR^L858R/T790M: 1 nM (IC₅₀); EGFR^L858R: 1 nM (IC₅₀); EGFR^L861Q: 6 nM (IC₅₀); EGFR: 25 nM (IC₅₀); ErbB4: 7 nM (IC₅₀); EGFR^{Exon 19 deletion/T790M}

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.