[논문]Synthesis and mutagenic risk of avanafil's potential genotoxic impurities

Sun, Yunkai; Wu, Xiaoxia; Zuo, Pei; Liu, Zhao; Miao, Xuepei; Liu, Jian; Wen, Hairuo

doi:10.1039/d4ra02345e

[해외논문] Synthesis and mutagenic risk of avanafil's potential genotoxic impurities

RSC advances, v.14 no.30, 2024년, pp.21432 - 21438

Sun, Yunkai (School of Chemical Engineering and Materials, Changzhou Institute of Technology, Changzhou 213022, China) , Wu, Xiaoxia (School of Chemistry and Chemical Engineering, University of South China, Hengyang 421001, China) , Zuo, Pei (Harvest Pharmaceutical Co., Ltd, Changsha 410000, China) , Liu, Zhao (Harvest Pharmaceutical Co., Ltd, Changsha 410000, China) , Miao, Xuepei (School of Chemical Engineering and Materials, Changzhou Institute of Technology, Changzhou 213022, China) , Liu, Jian (School of Chemical Engineering and Materials, Changzhou Institute of Technology, Changzhou 213022, China) , Wen, Hairuo (National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, Key Laboratory of Beijing for Nonclinical Safety Evaluation Research of Drugs, Beijing, 100176, P. R. China)

Abstract ▼ AI-Helper

In the technical route for the synthesis of avanafil, 1-ethyl-(3-dimethylaminopropyl)carbamyldiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole (HOBT) are used as reactive acid-amine binding agents. HOBT contains trace amounts of hydrazine residue, and there is a risk of introducing potentially mutagenic impurities with hydrazide-containing structures. The potentially genotoxic impurities E (Imp-E) and F (Imp-F) of avanafil with altering hydrazide-structure were synthesized by chemical method; subsequently, the impurities were evaluated and classified according to ICH M7 guidelines. Two complementary quantitative structure-activity relationship (QSAR) evaluation systems (Derek and Sarah) based on expert rules and statistics were used to preliminarily predict the genotoxicity of Imp-E and Imp-F, and the prediction result of E was suspected to be positive. In the Ames test of Imp-E and Imp-F, in the dose range of 62.5-1000 μg per plate, with or without the presence of metabolic activation system S9, the number of revertant colonies did not exceed 2 times the number of colonies in the solvent control group and did not show a dose-response relationship, and the test results were negative. Imp-E and Imp-F were determined to be negative for genotoxicity, which could be controlled as class 5 in ICH M7, that is, non mutagenic impurity.

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[해외논문] Synthesis and mutagenic risk of avanafil's potential genotoxic impurities

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[해외논문] Synthesis and mutagenic risk of avanafil's potential genotoxic impurities

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