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Safety Evaluation of N-((3S,4S)-4-(3,4-Difluorophenyl)piperidin-3-yl)-2-fluoro-4-(1-methyl-1H-pyrazol-5-yl) benzamide (Hu7691) by a Repeated Dose 14-Day Oral Exposure Toxicity Study in Rats
Gai, R.; Chen, C.; Zhang, W.; Ma, J.; Wang, X.; Chi, X.; Li, G. Safety and Toxicology Study of Hu7691, a Novel AKT Inhibitor, following Oral Administration in Rats. Toxics2023, 11, 880.
Gai, R.; Chen, C.; Zhang, W.; Ma, J.; Wang, X.; Chi, X.; Li, G. Safety and Toxicology Study of Hu7691, a Novel AKT Inhibitor, following Oral Administration in Rats. Toxics 2023, 11, 880.
Gai, R.; Chen, C.; Zhang, W.; Ma, J.; Wang, X.; Chi, X.; Li, G. Safety and Toxicology Study of Hu7691, a Novel AKT Inhibitor, following Oral Administration in Rats. Toxics2023, 11, 880.
Gai, R.; Chen, C.; Zhang, W.; Ma, J.; Wang, X.; Chi, X.; Li, G. Safety and Toxicology Study of Hu7691, a Novel AKT Inhibitor, following Oral Administration in Rats. Toxics 2023, 11, 880.
Abstract
Hu7691 represents a novel Pan-Akt kinase inhibitor, demonstrating excellent selectivity towards non-AGC kinase families and pronounced inhibitory effects on the proliferation of multiple tumor cell lines. However, there is currently a notable absence of in vivo toxicological research evidence concerning Hu7691. This study represents the first investigation into the 14-day repeated dose toxicity of Hu7691 in male and female Sprague-Dawley (SD) rats. Male rats were administered daily doses of 12.5, 50, 100, and 150 mg/kg, while female rats received doses of 12.5, 25, 50, and 75 mg/kg for 14 consecutive days. Hematological assessments, organ weights, and histopathological examinations revealed corresponding alterations, suggesting potential target organs for toxicity including the spleen, thymus, and gastrointestinal tract. It is worth noting that the test substance may also impact the liver, kidneys, heart, and ovaries. The No Observed Effect Level (NOAEL) was determined to be no greater than 12.5 mg/kg. Based on the observed gender-related toxicity differences in preliminary trials, it is recommended that the high dose reference dose for male animals in formal experiments should not be less than 100 mg/kg, while for female animals, it should be less than 50 mg/kg.
Medicine and Pharmacology, Pharmacology and Toxicology
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