5-HT2A antagonist 2 is an orally active, selective 5HT2A antagonist with an IC50 of 14 nM. It exhibits good chemical, hepatocyte, and plasma stability, without significant cytotoxicity in cell lines VERO, HFL-1, L929, NIH3T3, CHO-K1 [1].

5-HT 2A Receptor:14 nM

The compound 5-HT2A antagonist 2 administered orally at doses of 5-10 mg/kg daily for 12 weeks effectively countered high-fat diet (HFD)-induced metabolic syndrome associated steatohepatitis (MASLD) in C57BL6J mice [1]. The same dosage and administration method also significantly reduced liver fibrosis and inflammation in C57BL6/J mice fed with choline-deficient, L-amino acid-defined high-fat diet (CDAHFD) [1]. Moreover, pharmacokinetic properties of 5-HT2A antagonist 2 in rats and dogs were characterized as follows [1]: in rats, intravenous administration of 5 mg/kg resulted in a half-life of 4.4 hours, an AUC of 1.55 μg·h/mL, a clearance rate of 2.82 L/h/kg, and a volume of distribution of 8.86 L/kg; in dogs, the half-life after intravenous injection was 8.6 hours, AUC was 16.79 μg·h/mL, clearance rate was 0.42 L/h/kg, volume of distribution was 4.36 L/kg, and following oral administration, the AUC was 19.11 μg·h/mL with a bioavailability of 73%. The experimental models of C57BL6/J mice fed with HFD demonstrated significant reductions in liver and inguinal white adipose tissue (iWAT) fat mass and weight, improved glucose tolerance, and diminished hepatic steatosis, lobular inflammation, and hepatocyte ballooning. In CDAHFD-fed C57BL6/J mouse models, the same doses and administration reduced mRNA expression of col1a1 and α-SMA, as well as collagen accumulation and the expression of α-SMA, TNF-α, and IL-1β.