Toxicology profile of a novel GLP-1 receptor biased agonist-SAL0112 in nonhuman primates

Oral small-molecule GLP-1 receptor biased agonists exhibit promising treatment efficacy of type 2 diabetes and obesity. SAL0112 is a novel compound that has demonstrated remarkable efficacy in preclinical animal models. Herein, both in vitro and in vivo preclinical toxicity investigations were condu...

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Veröffentlicht in:Toxicology and applied pharmacology 2024-11, Vol.492, p.117125, Article 117125
Hauptverfasser: Sun, Jingchao, Xiao, Ying, Hu, Xuefeng, Chen, Shu, Huang, Jing, Ren, Zhiqiang, Luo, Binbin, Jiang, Rongzhi, Zhang, Hongmei, Shen, Xiaolei
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Sprache:eng
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Zusammenfassung:Oral small-molecule GLP-1 receptor biased agonists exhibit promising treatment efficacy of type 2 diabetes and obesity. SAL0112 is a novel compound that has demonstrated remarkable efficacy in preclinical animal models. Herein, both in vitro and in vivo preclinical toxicity investigations were conducted to explore the safety profile of SAL0112. The HTRF assay and TR-FRET assay were utilized for cAMP detection. Patch clamp assay was employed for hERG potassium ion channel determination. Cynomolgus monkeys were used in a cardiovascular safety pharmacology study and a 13-week repeated dose toxicity study. The telemetry system was employed to detect cardiovascular indicators such as ECG, HR, and BP. During the repeated dose toxicity study, body weight, food intake, hematology, coagulation function test, serum biochemistry tests, and urine analysis were measured. Macroscopic and microscopic observations were conducted at the end of the study. TK studies were conducted on Day 1 and Day 91. SAL0112 exhibited a high degree of potency in activating the monkey GLP-1 receptor whereas had no effect on the rodent GLP-1 receptor. In contrast to Danuglipron, which demonstrated high potency on hERG with an IC50 value of 6.9 μM, the IC50 of SAL0112 on hERG was greater than 100 μM. Compared to the Vehicle Control group, no significant changes in cardiovascular indicators were observed in the cardiovascular safety pharmacology study after a single dose of SAL0112 up to 250 mg/kg (P > 0.05). A repeated dose toxicity study revealed moderate anorexigenic effects and a reduction in body weight, effects that were found to be reversible and not associated with any pathological changes. The NOAEL of SAL0112 is 150 mg/kg, providing an approximate safety margin of threefold. SAL0112 demonstrated a favorable safety profile in cynomolgus monkeys, with a substantial therapeutic window that supports the progression of this compound into clinical studies. [Display omitted] •SAL0112 demonstrated good tolerance in Cynomolgus monkeys during a 13-week repeated doses toxicity study.•No liver toxicity was observed for SAL0112 in the repeated dose toxicity study.•SAL0112 offers a better cardiovascular safety profile compared to Danuglipron.
ISSN:0041-008X
1096-0333
1096-0333
DOI:10.1016/j.taap.2024.117125